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Aluksanasuwan S, Somsuan K, Wanna-Udom S, Roytrakul S, Morchang A, Rongjumnong A, Sakulsak N. Proteomic insights into the regulatory function of ARID1A in colon cancer cells. Oncol Lett 2024; 28:392. [PMID: 38966585 PMCID: PMC11223007 DOI: 10.3892/ol.2024.14525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/10/2024] [Indexed: 07/06/2024] Open
Abstract
The AT-rich interacting domain-containing protein 1A (ARID1A) is a tumor suppressor gene that has been implicated in several cancers, including colorectal cancer (CRC). The present study used a proteomic approach to elucidate the molecular mechanisms of ARID1A in CRC carcinogenesis. Stable ARID1A-overexpressing SW48 colon cancer cells were established using lentivirus transduction and the successful overexpression of ARID1A was confirmed by western blotting. Label-free quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry identified 705 differentially altered proteins in the ARID1A-overexpressing cells, with 310 proteins significantly increased and 395 significantly decreased compared with empty vector control cells. Gene Ontology enrichment analysis highlighted the involvement of the altered proteins mainly in the Wnt signaling pathway. Western blotting supported these findings, as a decreased protein expression of Wnt target genes, including c-Myc, transcription factor T cell factor-1/7 and cyclin D1, were observed in ARID1A-overexpressing cells. Among the altered proteins involved in the Wnt signaling pathway, the interaction network analysis revealed that ARID1A exhibited a direct interaction with E3 ubiquitin-protein ligase zinc and ring finger 3 (ZNRF3), a negative regulator of the Wnt signaling pathway. Further analyses using the The Cancer Genome Atlas colon adenocarcinoma public dataset revealed that ZNRF3 expression significantly impacted the overall survival of patients with CRC and was positively correlated with ARID1A expression. Finally, an increased level of ZNRF3 in ARID1A-overexpressing cells was confirmed by western blotting. In conclusion, the findings of the present study suggest that ARID1A negatively regulates the Wnt signaling pathway through ZNRF3, which may contribute to CRC carcinogenesis.
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Affiliation(s)
- Siripat Aluksanasuwan
- School of Medicine, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
- Cancer and Immunology Research Unit, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
| | - Keerakarn Somsuan
- School of Medicine, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
- Cancer and Immunology Research Unit, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
| | - Sasithorn Wanna-Udom
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Muang, Phitsanulok 65000, Thailand
| | - Sittiruk Roytrakul
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Klongluang, Pathum Thani 12120, Thailand
| | - Atthapan Morchang
- School of Medicine, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
- Cancer and Immunology Research Unit, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
| | - Artitaya Rongjumnong
- School of Medicine, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
- Cancer and Immunology Research Unit, Mae Fah Luang University, Muang, Chiang Rai 57100, Thailand
| | - Natthiya Sakulsak
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Muang, Phitsanulok 65000, Thailand
- Faculty of Medicine, Praboromarajchanok Institute, Ministry of Public Health, Mueang, Nonthaburi 11000, Thailand
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Marshall AH, Boyle DJ, Hanson MA, Nagarajan D, Bibi N, Safa A, Johantges AC, Wester JC. Arid1b haploinsufficiency in cortical inhibitory interneurons causes cell-type-dependent changes in cellular and synaptic development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.07.597984. [PMID: 38895260 PMCID: PMC11185764 DOI: 10.1101/2024.06.07.597984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Autism spectrum disorder (ASD) presents with diverse cognitive and behavioral abnormalities beginning during early development. Although the neural circuit mechanisms remain unclear, recent work suggests pathology in cortical inhibitory interneurons (INs) plays a crucial role. However, we lack fundamental information regarding changes in the physiology of synapses to and from INs in ASD. Here, we used transgenic mice to conditionally knockout one copy of the high confidence ASD risk gene Arid1b from the progenitors of parvalbumin-expressing fast-spiking (PV-FS) INs and somatostatin-expressing non-fast-spiking (SST-NFS) INs. In brain slices, we performed paired whole-cell recordings between INs and excitatory projection neurons (PNs) to investigate changes in synaptic physiology. In neonates, we found reduced synaptic input to INs but not PNs, with a concomitant reduction in the frequency of spontaneous network events, which are driven by INs in immature circuits. In mature mice, we found a reduction in the number of PV-FS INs in cortical layers 2/3 and 5. However, changes in PV-FS IN synaptic physiology were cortical layer and PN cell-type dependent. In layer 5, synapses from PV-FS INs to subcortical-projecting PNs were weakened. In contrast, in layer 2/3, synapses to and from PV-FS INs and corticocortical-projecting PNs were strengthened, leading to enhanced feedforward inhibition of input from layer 4. Finally, we found a novel synaptic deficit among SST-NFS INs, in which excitatory synapses from layer 2/3 PNs failed to facilitate. Our data highlight that changes in unitary synaptic dynamics among INs in ASD depend on neuronal cell-type.
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Marshall AH, Hanson MA, Boyle DJ, Nagarajan D, Bibi N, Fitzgerald J, Gaitten E, Kokiko-Cochran ON, Gu B, Wester JC. Arid1b haploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.04.597344. [PMID: 38895205 PMCID: PMC11185765 DOI: 10.1101/2024.06.04.597344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Arid1b is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work using transgenic mouse models suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. However, there is conflicting evidence regarding the relative roles of excitatory projection neurons and inhibitory interneurons in generating abnormal cognitive and behavioral phenotypes. Here, we conditionally knocked out either one or both copies of Arid1b from excitatory projection neuron progenitors and systematically investigated the effects on intrinsic membrane properties, synaptic physiology, social behavior, and seizure susceptibility. We found that disrupting Arid1b expression in excitatory neurons alters their membrane properties, including hyperpolarizing action potential threshold; however, these changes depend on neuronal subtype. Using paired whole-cell recordings, we found increased synaptic connectivity rate between projection neurons. Furthermore, we found reduced strength of excitatory synapses to parvalbumin (PV)-expression inhibitory interneurons. These data suggest an increase in the ratio of excitation to inhibition. However, the strength of inhibitory synapses from PV interneurons to excitatory neurons was enhanced, which may rebalance this ratio. Indeed, Arid1b haploinsufficiency in projection neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory projection neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.
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Zhang M, Guo T, Pei F, Feng J, Jing J, Xu J, Yamada T, Ho TV, Du J, Sehgal P, Chai Y. ARID1B maintains mesenchymal stem cell quiescence via inhibition of BCL11B-mediated non-canonical Activin signaling. Nat Commun 2024; 15:4614. [PMID: 38816354 PMCID: PMC11139927 DOI: 10.1038/s41467-024-48285-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 04/24/2024] [Indexed: 06/01/2024] Open
Abstract
ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs' quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.
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Affiliation(s)
- Mingyi Zhang
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Tingwei Guo
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Fei Pei
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jifan Feng
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Junjun Jing
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jian Xu
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Takahiko Yamada
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Thach-Vu Ho
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jiahui Du
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Prerna Sehgal
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA.
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Yamashita H, Nakayama K, Kanno K, Ishibashi T, Ishikawa M, Iida K, Razia S, Kiyono T, Kyo S. Evaluation of ARID1A as a Potential Biomarker for Predicting Response to Immune Checkpoint Inhibitors in Patients with Endometrial Cancer. Cancers (Basel) 2024; 16:1999. [PMID: 38893118 PMCID: PMC11171230 DOI: 10.3390/cancers16111999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND AT-rich interaction domain 1A (ARID1A) has been proposed as a new biomarker for predicting response to immune checkpoint inhibitors (ICIs). The predictive value of ARID1A for predicting ICI effectiveness has not been reported for endometrial cancer. Therefore, we investigated whether ARID1A negativity predicts ICI effectiveness for endometrial cancer treatment. METHODS We evaluated ARID1A expression, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunostaining endometrial samples from patients with endometrial cancer. Samples in which any of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) were determined to be negative via immunostaining were excluded. In the ARID1A-negative group, microsatellite instability (MSI) status was confirmed via MSI analysis. RESULTS Of the 102 samples investigated, 25 (24.5%) were ARID1A-negative. CD8 and PD-1 expression did not differ significantly between the ARID1A-negative group and the ARID1A-positive group; however, the ARID1A-negative group showed significantly lower PD-L1 expression. Only three samples (14.2%) in the ARID1A-negative group showed high MSI. Sanger sequencing detected three cases of pathological mutation in the MSH2-binding regions. We also established an ARID1A-knockout human ovarian endometriotic epithelial cell line (HMOsisEC7 ARID1A KO), which remained microsatellite-stable after passage. CONCLUSION ARID1A negativity is not suitable as a biomarker for ICI effectiveness in treating endometrial cancer.
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Affiliation(s)
- Hitomi Yamashita
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan; (H.Y.); (K.K.); (M.I.); (K.I.)
| | - Kentaro Nakayama
- Department of Obstetrics and Gynecology, Nagoya City University East Medical Centre, Nagoya 464-8547, Japan;
| | - Kosuke Kanno
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan; (H.Y.); (K.K.); (M.I.); (K.I.)
| | - Tomoka Ishibashi
- Department of Obstetrics and Gynecology, Nagoya City University East Medical Centre, Nagoya 464-8547, Japan;
| | - Masako Ishikawa
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan; (H.Y.); (K.K.); (M.I.); (K.I.)
| | - Kouji Iida
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan; (H.Y.); (K.K.); (M.I.); (K.I.)
| | - Sultana Razia
- Department of Legal Medicine, Shimane University School of Medicine, Izumo 693-8501, Japan;
| | - Tohru Kiyono
- Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa 277-8577, Japan;
| | - Satoru Kyo
- Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan; (H.Y.); (K.K.); (M.I.); (K.I.)
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Ragnarsson C, Yang M, Moura-Castro LH, Aydın E, Gunnarsson R, Olsson-Arvidsson L, Lilljebjörn H, Fioretos T, Duployez N, Zaliova M, Zuna J, Castor A, Johansson B, Paulsson K. Constitutional and acquired genetic variants in ARID5B in pediatric B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer 2024; 63:e23242. [PMID: 38738968 DOI: 10.1002/gcc.23242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/06/2024] [Accepted: 04/22/2024] [Indexed: 05/14/2024] Open
Abstract
Constitutional polymorphisms in ARID5B are associated with an increased risk of developing high hyperdiploid (HeH; 51-67 chromosomes) pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). Here, we investigated constitutional and somatic ARID5B variants in 1335 BCP ALL cases from five different cohorts, with a particular focus on HeH cases. In 353 HeH ALL that were heterozygous for risk alleles and trisomic for chromosome 10, where ARID5B is located, a significantly higher proportion of risk allele duplication was seen for the SNPs rs7090445 (p = 0.009), rs7089424 (p = 0.005), rs7073837 (p = 0.03), and rs10740055 (p = 0.04). Somatic ARID5B deletions were seen in 16/1335 cases (1.2%), being more common in HeH than in other genetic subtypes (2.2% vs. 0.4%; p = 0.002). The expression of ARID5B in HeH cases with genomic deletions was reduced, consistent with a functional role in leukemogenesis. Whole-genome sequencing and RNA-sequencing in HeH revealed additional somatic events involving ARID5B, resulting in a total frequency of 3.6% of HeH cases displaying a somatic ARID5B aberration. Overall, our results show that both constitutional and somatic events in ARID5B are involved in the leukemogenesis of pediatric BCP ALL, particularly in the HeH subtype.
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Affiliation(s)
- Charlotte Ragnarsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Department of Paediatrics, Skåne University Hospital, Lund University, Lund, Sweden
| | - Minjun Yang
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | | | - Efe Aydın
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Rebeqa Gunnarsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Linda Olsson-Arvidsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden
| | - Henrik Lilljebjörn
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Thoas Fioretos
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden
| | - Nicolas Duployez
- Laboratory of Haematology, Centre Hospitalier Universitaire (CHU) Lille, University of Lille, INSERM Unité 1277 Canther, Lille, France
| | - Marketa Zaliova
- Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
- Childhood Leukaemia Investigation Prague (CLIP), Prague, Czech Republic
| | - Jan Zuna
- Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
- Childhood Leukaemia Investigation Prague (CLIP), Prague, Czech Republic
| | - Anders Castor
- Department of Paediatrics, Skåne University Hospital, Lund University, Lund, Sweden
| | - Bertil Johansson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden
| | - Kajsa Paulsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
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Hinsberger M, Becker-Kettern J, Jürgens-Wemheuer WM, Oertel J, Schulz-Schaeffer WJ. Development of an Enzyme-Linked Immunosorbent Assay (ELISA) for the Quantification of ARID1A in Tissue Lysates. Cancers (Basel) 2023; 15:4096. [PMID: 37627124 PMCID: PMC10452747 DOI: 10.3390/cancers15164096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/10/2023] [Accepted: 08/13/2023] [Indexed: 08/27/2023] Open
Abstract
ARID1A is a subunit of the mammalian SWI/SNF complex, which is thought to regulate gene expression through restructuring chromatin structures. Its gene ARID1A is frequently mutated and ARID1A levels are lowered in several human cancers, especially gynecologic ones. A functional ARID1A loss may have prognostic or predictive value in terms of therapeutic strategies but has not been proposed based on a quantitative method. Hardly any literature is available on ARID1A levels in tumor samples. We developed an indirect enzyme-linked immunosorbent assay (ELISA) for ARID1A based on the current EMA and FDA criteria. We demonstrated that our ELISA provides the objective, accurate, and precise quantification of ARID1A concentrations in recombinant protein solutions, cell culture standards, and tissue lysates of tumors. A standard curve analysis yielded a 'goodness of fit' of R2 = 0.99. Standards measured on several plates and days achieved an inter-assay accuracy of 90.26% and an inter-assay precision with a coefficient of variation of 4.53%. When tumor lysates were prepared and measured multiple times, our method had an inter-assay precision with a coefficient of variation of 11.78%. We believe that our suggested method ensures a high reproducibility and can be used for a high sample throughput to determine the ARID1A concentration in different tumor entities. The application of our ELISA on various tumor and control tissues will allow us to explore whether quantitative ARID1A measurements in tumor samples are of predictive value.
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Affiliation(s)
- Manuel Hinsberger
- Institute for Neuropathology, Medical Faculty, Saarland University, Building 90.3, 66421 Homburg, Saar, Germany (J.B.-K.); (W.M.J.-W.)
| | - Julia Becker-Kettern
- Institute for Neuropathology, Medical Faculty, Saarland University, Building 90.3, 66421 Homburg, Saar, Germany (J.B.-K.); (W.M.J.-W.)
| | - Wiebke M. Jürgens-Wemheuer
- Institute for Neuropathology, Medical Faculty, Saarland University, Building 90.3, 66421 Homburg, Saar, Germany (J.B.-K.); (W.M.J.-W.)
| | - Joachim Oertel
- Department of Neurosurgery, Medical Faculty, Saarland University, Building 90.3, 66421 Homburg, Saar, Germany;
| | - Walter J. Schulz-Schaeffer
- Institute for Neuropathology, Medical Faculty, Saarland University, Building 90.3, 66421 Homburg, Saar, Germany (J.B.-K.); (W.M.J.-W.)
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Schraml P, Aimi F, Zoche M, Aguilera‐Garcia D, Arnold F, Moch H, Hottiger MO. Altered cytoplasmic and nuclear ADP-ribosylation levels analyzed with an improved ADP-ribose binder are a prognostic factor in renal cell carcinoma. J Pathol Clin Res 2023; 9:273-284. [PMID: 36999983 PMCID: PMC10240151 DOI: 10.1002/cjp2.320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/03/2023] [Accepted: 03/10/2023] [Indexed: 04/01/2023]
Abstract
ADP-ribosylation (ADPR) of proteins is catalyzed by ADP-ribosyltransferases, which are targeted by inhibitors (i.e. poly(ADP-ribose) polymerase inhibitors [PARPi]). Although renal cell carcinoma (RCC) cells are sensitive in vitro to PARPi, studies on the association between ADPR levels and somatic loss of function mutations in DNA damage repair genes are currently missing. Here we observed, in two clear cell RCC (ccRCC) patient cohorts (n = 257 and n = 241) stained with an engineered ADP-ribose binding macrodomain (eAf1521), that decreased cytoplasmic ADPR (cyADPR) levels significantly correlated with late tumor stage, high-ISUP (the International Society of Urological Pathology) grade, presence of necrosis, dense lymphocyte infiltration, and worse patient survival (p < 0.01 each). cyADPR proved to be an independent prognostic factor (p = 0.001). Comparably, absence of nuclear ADPR staining in ccRCC correlated with absence of PARP1 staining (p < 0.01) and worse patient outcome (p < 0.05). In papillary RCC the absence of cyADPR was also significantly associated with tumor progression and worse patient outcome (p < 0.05 each). To interrogate whether the ADPR status could be associated with genetic alterations in DNA repair, chromatin remodeling, and histone modulation, we performed DNA sequence analysis and identified a significant association of increased ARID1A mutations in ccRCCcyADPR+++/PARP1+ compared with ccRCCcyADPR-/PARP1- (31% versus 4%; p < 0.05). Collectively, our data suggest the prognostic value of nuclear and cytoplasmic ADPR levels in RCC that might be further influenced by genetic alterations.
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Affiliation(s)
- Peter Schraml
- Department of Pathology and Molecular PathologyUniversity Hospital Zurich (USZ)ZurichSwitzerland
| | - Fabio Aimi
- Department of Pathology and Molecular PathologyUniversity Hospital Zurich (USZ)ZurichSwitzerland
- Department of Molecular Mechanism of Disease (DMMD)University of Zurich (UZH)ZurichSwitzerland
| | - Martin Zoche
- Department of Pathology and Molecular PathologyUniversity Hospital Zurich (USZ)ZurichSwitzerland
| | - Domingo Aguilera‐Garcia
- Department of Pathology and Molecular PathologyUniversity Hospital Zurich (USZ)ZurichSwitzerland
| | - Fabian Arnold
- Department of Pathology and Molecular PathologyUniversity Hospital Zurich (USZ)ZurichSwitzerland
| | - Holger Moch
- Department of Pathology and Molecular PathologyUniversity Hospital Zurich (USZ)ZurichSwitzerland
| | - Michael O Hottiger
- Department of Molecular Mechanism of Disease (DMMD)University of Zurich (UZH)ZurichSwitzerland
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9
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Momeni-Boroujeni A, Vanderbilt C, Yousefi E, Abu-Rustum NR, Aghajanian C, Soslow RA, Ellenson LH, Weigelt B, Murali R. Landscape of chromatin remodeling gene alterations in endometrial carcinoma. Gynecol Oncol 2023; 172:54-64. [PMID: 36958196 PMCID: PMC10192087 DOI: 10.1016/j.ygyno.2023.03.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 02/01/2023] [Accepted: 03/15/2023] [Indexed: 03/25/2023]
Abstract
OBJECTIVE Chromatin remodeling genes (CRGs) encode components of epigenetic regulatory mechanisms and alterations in these genes have been identified in several tumor types, including gynecologic cancers. In this study, we sought to investigate the prevalence and clinicopathological associations of CRG alterations in endometrial carcinoma (EC). METHODS We performed a retrospective analysis of 660 ECs sequenced using a clinical massively parallel sequencing assay targeting up to 468 genes, including 25 CRGs, and defined the presence of somatic CRG alterations. Clinicopathologic features were obtained for all cases. Immunohistochemical interrogation of ARID1A and PTEN proteins was performed in a subset of samples. RESULTS Of the 660 ECs sequenced, 438 (66.4%) harbored CRG alterations covered by our panel. The most commonly altered CRG was ARID1A (46%), followed by CTCF (21%), KMT2D (18%), KMT2B (17%), BCOR (16%), ARID1B (12%) and SMARCA4 (11%). We found that ARID1A genetic alterations were preferentially bi-allelic and often corresponded to altered ARID1A protein expression in ECs. We further observed that ARID1A alterations were often subclonal when compared to PTEN alterations, which were primarily clonal in ECs harboring both mutations. Finally, CRG alterations were associated with an increased likelihood of myometrial and lymphovascular invasion in endometrioid ECs. CONCLUSION CRG alterations are common in EC and are associated with clinicopathologic features and likely play a crucial role in EC.
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Affiliation(s)
- Amir Momeni-Boroujeni
- Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Chad Vanderbilt
- Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Elham Yousefi
- Department of Pathology and Cell Biology, Columbia University Irvine Medical Center, New York, NY, United States of America
| | - Nadeem R Abu-Rustum
- Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Carol Aghajanian
- Departments of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Robert A Soslow
- Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Lora H Ellenson
- Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Britta Weigelt
- Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Rajmohan Murali
- Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
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10
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Sun D, Zhao H, Zhou H, Tao J, Li T, Zhu J, Hou H. ARID1A deficiency associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes predicts a good prognosis of endometrial carcinoma. Transl Oncol 2023; 33:101685. [PMID: 37137217 PMCID: PMC10176062 DOI: 10.1016/j.tranon.2023.101685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 04/11/2023] [Accepted: 04/28/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND ARID1A alterations have been detected in 40% of endometrial carcinomas (ECs) and are associated with loss of its expression. The role of ARID1A in tumorigenesis and development is complex, and the prognostic role in EC remains controversial. Hence, it is of great significance to confirm the role of ARID1A in EC. METHODS A total of 549 EC patients (cohort A) from TCGA were evaluated to explore the prognostic role of ARID1A. NGS was performed for 13 EC patients (cohort B), and expression of ARID1A, CD3, CD8 and mismatch repair (MMR) proteins in 52 patients (cohort C) from our center was determined by immunohistochemistry (IHC). The Kaplan-Meier method was used to perform survival analyses. RESULTS ARID1A alterations were detected in 32% of EC patients and correlated with good disease-free survival (DFS, P = 0.004) and overall survival (OS, P = 0.0353). ARID1A alterations were found to co-occur with MMR-related gene mutations and correlated with higher PD-L1 expression. Patients concomitantly harboring ARID1A alterations and MMR-related gene mutations had the best prognosis (DFS: P = 0.0488; OS: P = 0.0024). A cohort from our center showed that ARID1A deficiency was an independent prognostic factor and predicted longer recurrence-free survival (P = 0.0476). ARID1A loss was associated with a tendency toward MSI-H (P = 0.0060). ARID1A alterations and expression loss were associated with a higher abundance of CD3+ (P = 0.0406) and CD8+ (P = 0.0387) T cells. CONCLUSION ARID1A alterations and expression loss are tightly associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes, which might contribute to the good prognosis of EC.
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Affiliation(s)
- Dantong Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Han Zhao
- Department of Pathology, The Affiliated Hospital of Qingdao University, 266000, Qingdao, China
| | - Hai Zhou
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Junyan Tao
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Tianjun Li
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Jingjuan Zhu
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Helei Hou
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
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11
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Bryzgalov LO, Korbolina EE, Merkulova TI. Exploring the Genetic Predisposition to Epigenetic Changes in Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24097955. [PMID: 37175659 PMCID: PMC10177989 DOI: 10.3390/ijms24097955] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/05/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Alzheimer's disease (AD) is a prevalent type of dementia in elderly populations with a significant genetic component. The accumulating evidence suggests that AD involves a reconfiguration of the epigenetic landscape, including DNA methylation, post-translational modification of histone proteins, and chromatin remodeling. Along with environmental factors, individual specific genetic features play a considerable role in the formation of epigenetic architecture. In this study, we attempt to identify the non-coding regulatory SNPs (rSNPs) able to affect the epigenetic mechanisms in AD. To this end, the multi-omics approach is used. The GEO (Gene Expression Omnibus) available data (GSE153875) for AD patients and controls are integrated to reveal the rSNPs that display allele-specific features in both ChIP-seq profiles of four histone modifications and RNA-seq. Furthermore, we analyze the presence of rSNPs in the promoters of genes reported to be differentially expressed between AD and the normal brain (AD-related genes) and involved in epigenetic regulation according to the EpiFactors database. We also searched for the rSNPs in the promoters of the genes coding for transcription regulators of the identified AD-related genes. These regulators were selected based on the corresponding ChIP-seq peaks (ENCODE) in the promoter regions of these genes. Finally, we formed a panel of rSNPs localized to the promoters of genes that contribute to the epigenetic landscape in AD and, thus, to the genetic predisposition for this disease.
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Affiliation(s)
- Leonid O Bryzgalov
- The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Science, 10 Lavrentyeva Prospekt, 630090 Novosibirsk, Russia
- Vector-Best, 630117 Novosibirsk, Russia
| | - Elena E Korbolina
- The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Science, 10 Lavrentyeva Prospekt, 630090 Novosibirsk, Russia
| | - Tatiana I Merkulova
- The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Science, 10 Lavrentyeva Prospekt, 630090 Novosibirsk, Russia
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12
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Zhang Y, Chen M, Huang D, Gu H, Yi Y, Meng X. Correlation between ARID1B gene mutation (p.A460, p.V215G) and prognosis of high-risk refractory neuroblastoma. Cell Biol Int 2023. [PMID: 36883912 DOI: 10.1002/cbin.12013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 02/12/2023] [Accepted: 02/25/2023] [Indexed: 03/09/2023]
Abstract
In a few reports, ARID1B/A mutation was found in neuroblastoma. We analyzed the clinical characteristics, clinical efficacy, and prognosis of three children with high-risk refractory neuroblastoma (NB) with somatic ARID1B gene mutation. The whole exon sequencing results showed that there were involved in transcription, DNA synthesis, and repair of ARID1B gene mutations. All mutation sites were located in the promoter region of the exon: ARID1B (p.A460) mutation was found in cases 1 and 2, and ARID1B (p.V215G) mutation was found in cases 1 and 3. The nucleic acid site of ARID1B (p.A460) mutation was c.1379 (exon1) C > G, and the nucleic acid site of ARID1B (p.V215G) mutation was c.644 (exon1) T > G. The meningeal metastasis in case 1 turned negative after 4 cycles of intrathecal injection combined with chemotherapy. However, the child died of agranulocytosis combined with sepsis during the 5th cycle of chemotherapy. Case 2 achieved complete remission (CR). Case 3 achieved CR after chemotherapy, surgery, metaiodobenzylguanidine, and 3F-8 (Naxitamab) immunotherapy after the initial diagnosis. The mediastinum and lymph node metastasis occurred during the 6-month observation period after stopping treatment. He achieved very good partial remission after individualized chemotherapy and surgical treatment. ARID1B is a component protein of the SWI/SNF chromatin-remodeling complex that participates in the occurrence of a variety of tumors by regulating DNA repair and synthesis. ARID1B nucleic acid mutation (p.A460, p.V215G) in the promoter region of three children may contribute to the poor prognosis of NB children.
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Affiliation(s)
- Yi Zhang
- Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Moyi Chen
- Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Dongsheng Huang
- Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Huali Gu
- Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - You Yi
- Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Xue Meng
- Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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13
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Reddy D, Bhattacharya S, Levy M, Zhang Y, Gogol M, Li H, Florens L, Workman JL. Paraspeckles interact with SWI/SNF subunit ARID1B to regulate transcription and splicing. EMBO Rep 2023; 24:e55345. [PMID: 36354291 PMCID: PMC9827562 DOI: 10.15252/embr.202255345] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 10/12/2022] [Accepted: 10/20/2022] [Indexed: 11/12/2022] Open
Abstract
Paraspeckles are subnuclear RNA-protein structures that are implicated in important processes including cellular stress response, differentiation, and cancer progression. However, it is unclear how paraspeckles impart their physiological effect at the molecular level. Through biochemical analyses, we show that paraspeckles interact with the SWI/SNF chromatin-remodeling complex. This is specifically mediated by the direct interaction of the long-non-coding RNA NEAT1 of the paraspeckles with ARID1B of the cBAF-type SWI/SNF complex. Strikingly, ARID1B depletion, in addition to resulting in loss of interaction with the SWI/SNF complex, decreases the binding of paraspeckle proteins to chromatin modifiers, transcription factors, and histones. Functionally, the loss of ARID1B and NEAT1 influences the transcription and the alternative splicing of a common set of genes. Our findings reveal that dynamic granules such as the paraspeckles may leverage the specificity of epigenetic modifiers to impart their regulatory effect, thus providing a molecular basis for their function.
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Affiliation(s)
- Divya Reddy
- Stowers Institute for Medical ResearchKansas CityMOUSA
| | | | | | - Ying Zhang
- Stowers Institute for Medical ResearchKansas CityMOUSA
| | | | - Hua Li
- Stowers Institute for Medical ResearchKansas CityMOUSA
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14
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Zhu Y, Yan C, Wang X, Xu Z, Lv J, Xu X, Yu W, Zhou M, Yue L. Pan-cancer analysis of ARID family members as novel biomarkers for immune checkpoint inhibitor therapy. Cancer Biol Ther 2022; 23:104-111. [PMID: 35239432 PMCID: PMC8896200 DOI: 10.1080/15384047.2021.2011643] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Although immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment, the accuracy of predictive biomarkers for ICI outcomes, such as PD-L1, TMB (tumor mutation burden) or MMR (mismatch repair) deficiency, have not been satisfactory. ARID family members are essential for maintaining the basic process of genomic stability and may serve as novel biomarkers for ICI therapy. A total of 1660 cancer patients who received ICI therapy were included in this pan-cancer analysis. The basic information and TMB values of each patient were collected. Survival analysis based on the Kaplan-Meier (KM) method was performed to explore the relationships between mutations in ARID family members and prognosis in pan-cancer as well as cancer subtypes. Genetic alterations in ARID1A (12%), ARID1B (5%), ARID2 (6%) and ARID5B (2.6%) were identified in multiple cancer types. Patients harboring mutated ARID family members benefited more from ICI therapy (P = .0003). Mutated ARID1A (P = .01), ARID1B (P = .0097) and ARID2 (P = .0054) all serve as compelling biomarkers in predicting the prognosis of ICI treatment. In addition, members of the ARID family were found to be strongly related to the abundance of CD4 + T cells and CD8 + T cells, the expression of PD-L1 and the TMB value in various cancers. Specifically, members of the ARID family could serve as novel biomarkers in multiple malignancies, especially gastrointestinal cancers. ARID family members serve as novel biomarkers for ICI therapy in malignancies. Testing the genomic status of ARID family members could help identify the definite subpopulation that benefits most from ICI treatment.Abbreviations: AT-rich interactive domain (ARID)Switch/sucrose nonfermenting (SWI/SNF)Non-small cell lung cancer (NSCLC)Immune checkpoint inhibitors (ICIs)Tumor microenvironment (TME)Programmed death-ligand 1 (PD-L1)Tumor mutational burden (TMB).
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Affiliation(s)
- Yan Zhu
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Chun Yan
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Xiaofei Wang
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Zhijian Xu
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Jianjian Lv
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Xiaomei Xu
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Wenjun Yu
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Mi Zhou
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Lu Yue
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
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15
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Li X, Feng C, Peng S. Epigenetics alternation in lung fibrosis and lung cancer. Front Cell Dev Biol 2022; 10:1060201. [PMID: 36420141 PMCID: PMC9676258 DOI: 10.3389/fcell.2022.1060201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 10/20/2022] [Indexed: 09/10/2023] Open
Abstract
Respiratory disease including interstitial lung diseases (ILDs) and lung cancer is a group of devastating diseases that linked with increased morbidity and healthcare burden. However, respiratory diseases cannot be fully explained by the alternation of genetic information. Genetic studies described that epigenetic mechanisms also participate to transmit genetic information. Recently, many studies demonstrated the role of altered epigenetic modification in the pathogenesis of lung cancer and pulmonary fibrosis. Due to lacking effective medication, the underlying pathophysiological processes and causal relationships of lung diseases with epigenetic mechanisms still need to be better understood. Our present review provided a systematic revision of current knowledge concerning diverse epigenetic aberrations in major lung diseases, with special emphasis on DNA methylation, histone modifications, lncRNAs profiles, telomere patterns, as well as chromatin-remodelling complexes. We believed that a new target therapy for lung disease based on findings of the involved epigenetic pathway is a promising future direction.
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Affiliation(s)
- Xueren Li
- Department of Respiratory Medicine, Tianjin Haihe Hospital, Tianjin, China
- Tianjin Institute of Respiratory Diseases, Tianjin, China
| | - Chunjing Feng
- The Institute Includes H&B(Tianjin) Stem Cell Research Institute, Tianjin, China
| | - Shouchun Peng
- Department of Respiratory Medicine, Tianjin Haihe Hospital, Tianjin, China
- Tianjin Institute of Respiratory Diseases, Tianjin, China
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16
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Sun D, Qian H, Wang J, Xie T, Teng F, Li J, Xing P. ARID1A deficiency reverses the response to anti-PD(L)1 therapy in EGFR-mutant lung adenocarcinoma by enhancing autophagy-inhibited type I interferon production. Cell Commun Signal 2022; 20:156. [PMID: 36229854 PMCID: PMC9558404 DOI: 10.1186/s12964-022-00958-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/14/2022] [Indexed: 12/01/2022] Open
Abstract
INTRODUCTION EGFR mutations in non-small cell lung cancer (NSCLC) are associated with a poor response to immune checkpoint inhibitors (ICIs), and only 20% of NSCLC patients harboring EGFR mutations benefit from immunotherapy. Novel biomarkers or therapeutics are needed to predict NSCLC prognosis and enhance the efficacy of ICIs in NSCLC patients harboring EGFR mutations, especially lung adenocarcinoma (LUAD) patients, who account for approximately 40-50% of all NSCLC cases. METHODS An ARID1A-knockdown (ARID1A-KD) EGFR-mutant LUAD cell line was constructed using lentivirus. RNA-seq and mass spectrometry were performed. Western blotting and IHC were used for protein expression evaluation. Effects of 3-MA and rapamycin on cells were explored. Immunofluorescence assays were used for immune cell infiltration examination. RESULTS ARID1A expression was negatively associated with immune cell infiltration and immune scores for ICIs in LUAD with EGFR mutations. In vitro experiments suggested that ARID1A-KD activates the EGFR/PI3K/Akt/mTOR pathway and inhibits autophagy, which attenuates the inhibition of Rig-I-like receptor pathway activity and type I interferon production in EGFR-mutant LUAD cells. In addition, 3-MA upregulated production of type I interferon in EGFR-mutant LUAD cells, with an similar effect to ARID1A-KD. On the other hand, rapamycin attenuated the enhanced production of type I interferon in ARID1A-KD EGFR-mutant LUAD cells. ARID1A function appears to influence the tumor immune microenvironment and response to ICIs. CONCLUSION ARID1A deficiency reverses response to ICIs in EGFR-mutant LUAD by enhancing autophagy-inhibited type I interferon production. Video Abstract.
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Affiliation(s)
- Dantong Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Haili Qian
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Jinsong Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Tongji Xie
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Fei Teng
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Junling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Puyuan Xing
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
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17
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Tan Y, Chen J, Li Y, Liu Y, Wang Y, Xia S, Chen L, Wei W, Chen Z. Three Novel ARID1B Variations in Coffin-Siris Syndrome Patients. Neurol India 2022; 70:2174-2179. [PMID: 36352633 DOI: 10.4103/0028-3886.359283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Coffin-Siris syndrome (CSS) (OMIM #135900) involves multiple congenital malformations, including hypotonia, short stature, sparse scalp hair, a coarse face, prominent eyebrows, a wide mouth, delayed bone age, and hypoplastic or absent fifth fingers/toes or nails, together with developmental delay. The cause of CSS is suggested to be related to alterations in the BRG- or HRBM-associated factor (BAF) pathway in humans. In this gene family, pathogenic variations in the AT-rich interactive domain-containing protein 1B (ARID1B) gene are revealed to be a significant element causing neurodevelopmental disability in patients with CSS. Herein, we describe the clinical features and gene variations in four Chinese patients with CSS. All the patients shared common features of short fifth fingers/toes or hypoplastic nails, coarse facial features, thick eyebrows, long cilia, a flat nasal bridge, a broad nose, a wide mouth, a high palate, and hypotonia. Besides, they had an intellectual disability, language, and motor developmental delay. Candidate genes were screened for variations using polymerase chain reaction (PCR) and sequencing. The variations were sequenced by next-generation sequencing and confirmed by first-generation sequencing. Exome sequencing suggested four de novo variations in the ARID1B gene in four unrelated patients. These included two frameshift variations (c.3581delC, c.6661_6662insG) and two nonsense variations (c.1936C>T, c.2248C>T). Of the four variations, three variations were novel. The results in our present study broaden the understanding of the disease and further interpret the molecular genetic mechanism of these rare variations in CSS.
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Affiliation(s)
- Yuxia Tan
- Department of Pediatrics, The Affiliated Hospital of Qingdao University, Haier Road; Department of Pediatrics, Zibo City Maternal and Child Health Hospital, Zibo City, Shandong Province, Qingdao, Shandong, 266034, China
| | - Jun Chen
- Department of Neurology and Rehabilitation, Qingdao Women and Children's Hospital, Qingdao University. No. 6 Tongfu Road, Qingdao, Shandong, 266034, China
| | - Yutang Li
- Department of Neurology and Rehabilitation, Qingdao Women and Children's Hospital, Qingdao University. No. 6 Tongfu Road, Qingdao, Shandong, 266034, China
| | - Yedan Liu
- Department of Pediatrics, The Affiliated Hospital of Qingdao University, Haier Road, Qingdao, Shandong, 266034, China
| | - Yu Wang
- Department of Pediatrics, Zibo City Maternal and Child Health Hospital, Zibo City, Shandong Province, China
| | - Shungang Xia
- Department of Pediatrics, Zibo City Maternal and Child Health Hospital, Zibo City, Shandong Province, China
| | - Liping Chen
- Department of Pediatrics, Zibo City Maternal and Child Health Hospital, Zibo City, Shandong Province, China
| | - Wei Wei
- Beijing Kangso Medical Inspection Co., Ltd, Building 10, Zone C, Yiyuan Science and Technology Park Haidian District. No. 65 Xingshikou Road, Beijing, 100195, China
| | - Zongbo Chen
- Department of Pediatrics, The Affiliated Hospital of Qingdao University, Haier Road, Qingdao, Shandong, 266034, China
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18
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Kumar S, Baranwal VK, Haile MT, Oualim KMZ, Abatiyow BA, Kennedy SY, Vaughan AM, Kappe SHI. PfARID Regulates P. falciparum Malaria Parasite Male Gametogenesis and Female Fertility and Is Critical for Parasite Transmission to the Mosquito Vector. mBio 2022; 13:e0057822. [PMID: 35638735 PMCID: PMC9239086 DOI: 10.1128/mbio.00578-22] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/09/2022] [Indexed: 11/20/2022] Open
Abstract
Sexual reproduction of Plasmodium falciparum parasites is critical to the spread of malaria in the human population. The factors that regulate gene expression underlying formation of fertilization-competent gametes, however, remain unknown. Here, we report that P. falciparum expresses a protein with an AT-rich interaction domain (ARID) which, in other organisms, is part of chromatin remodeling complexes. P. falciparum ARID (PfARID) localized to the parasite nucleus and is critical for the formation of male gametes and fertility of female gametes. PfARID gene deletion (Pfarid-) gametocytes showed downregulation of gene expression important for gametogenesis, antigenic variation, and cell signaling and for parasite development in the mosquito. Our study identifies PfARID as a critical nuclear protein involved in regulating the gene expression landscape of mature gametocytes. This establishes fertility and also prepares the parasite for postfertilization events that are essential for infection of the mosquito vector. IMPORTANCE Successful completion of the Plasmodium life cycle requires formation of mature gametocytes and their uptake by the female Anopheles mosquito vector in an infected blood meal. Inside the mosquito midgut the parasite undergoes gametogenesis and sexual reproduction. In the present study, we demonstrate that PfARID is essential for male gametogenesis and female fertility and, thereby, transmission to the mosquito vector. PfARID possibly regulates the chromatin landscape of stage V gametocytes and targeting PfARID function may provide new avenues into designing interventions to prevent malaria transmission.
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Affiliation(s)
- Sudhir Kumar
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
| | - Vinay K. Baranwal
- Molecular Botany Lab, Swami Devanand Post Graduate College, Math-Lar, Deoria, Uttar Pradesh, India
| | - Meseret T. Haile
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
| | - Kenza M. Z. Oualim
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
| | - Biley A. Abatiyow
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
| | - Spencer Y. Kennedy
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
| | - Ashley M. Vaughan
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
- Department of Pediatrics, University of Washington, Seattle, Washington, USA
| | - Stefan H. I. Kappe
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
- Department of Pediatrics, University of Washington, Seattle, Washington, USA
- Department of Global Health, University of Washington, Seattle, Washington, USA
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19
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Yu C, Lei X, Chen F, Mao S, Lv L, Liu H, Hu X, Wang R, Shen L, Zhang N, Meng Y, Shen Y, Chen J, Li P, Huang S, Lin C, Zhang Z, Yuan K. ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription. Nat Commun 2022; 13:3501. [PMID: 35715442 PMCID: PMC9205910 DOI: 10.1038/s41467-022-31197-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 06/07/2022] [Indexed: 11/25/2022] Open
Abstract
Transposable elements (TEs) through evolutionary exaptation have become an integral part of the human genome, offering ample regulatory sequences and shaping chromatin 3D architecture. While the functional impacts of TE-derived sequences on early embryogenesis have been recognized, their roles in malignancy are only starting to emerge. Here we show that many TEs, especially the pluripotency-related human endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. Transcriptional upregulation of HERVH is associated with mutations of several tumor suppressors, particularly ARID1A. Knockout of ARID1A in CRC cells leads to increased transcription at several HERVH loci, which involves compensatory contribution by ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Mechanistically, HERVH transcripts colocalize with nuclear BRD4 foci, modulating their dynamics and co-regulating many target genes. Altogether, we uncover a critical role for ARID1A in restraining HERVH, whose abnormal activation can promote tumorigenesis by stimulating BRD4-dependent transcription. Here the authors show mutation of the BAF chromatin remodeler subunit ARID1A results in an ARID1B-dependent upregulation of HERVH, an ERV required for the pluripotency regulatory network. These HERVH RNAs can partition into BRD4 foci, affecting BRD4-dependent transcription. Suppression of HERVH in colorectal cancer cells and patient-derived organoids impairs tumor growth.
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Affiliation(s)
- Chunhong Yu
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoyun Lei
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fang Chen
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Song Mao
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lu Lv
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Honglu Liu
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xueying Hu
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Runhan Wang
- Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Licong Shen
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Na Zhang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yang Meng
- Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Yunfan Shen
- Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Jiale Chen
- Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Pishun Li
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shi Huang
- Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Changwei Lin
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Gastrointestinal Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhuohua Zhang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Kai Yuan
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,The Biobank of Xiangya Hospital, Central South University, Changsha, Hunan, China.
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20
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Ren D, Wei X, Lin L, Yuan F, Bi Y, Guo Z, Liu L, Ji L, Yang X, Han K, Yang F, Wu X, Li X, Yi Z, Xu Y, Cai C, Wang P, Li W, He L, Zhou D, Yu T, Shi Y, Lu Q, He G. A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity. Mol Psychiatry 2022; 27:2777-2786. [PMID: 35365808 DOI: 10.1038/s41380-022-01530-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 03/10/2022] [Accepted: 03/16/2022] [Indexed: 11/08/2022]
Abstract
ARID4A plays an important role in regulating gene expression and cell proliferation. ARID4A belongs to the AT-rich interaction domain (ARID)-containing family, and a PWWP domain immediately precedes its ARID region. The molecular mechanism and structural basis of ARID4A are largely unknown. Whole-exome sequencing (WES) revealed that a novel heterozygous missense variant, ARID4A c.1231 C > G (p.His411Asp), was associated with schizophrenia (SCZ) in this study. We determined the crystal structure of the PWWP-ARID tandem at 2.05 Å, revealing an unexpected mode in which ARID4A assembles with its PWWP and ARID from a structural and functional supramodule. Our results further showed that compared with the wild type, the p.His411Asp ARID mutant protein adopts a less compact conformation and exhibits a weaker dsDNA-binding ability. The p.His411Asp mutation decreased the number of cells that were arrested in the G0-G1 phase and caused more cells to progress to the G2-M phase. In addition, the missense mutation promoted the proliferation of HEK293T cells. In conclusion, our data provide evidence that ARID4A p.His411Asp could cause a conformational change in the ARID4A ARID domain, influence the DNA binding function, and subsequently disturb the cell cycle arrest in the G1 phase. ARID4A is likely a susceptibility gene for SCZ; thus, these findings provide new insight into the role of ARID4A in psychiatric disorders.
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Affiliation(s)
- Decheng Ren
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxi Wei
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Lin
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fan Yuan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Bi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenming Guo
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liangjie Liu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Ji
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ke Han
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fengping Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Wu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingwang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenghui Yi
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yifeng Xu
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changqun Cai
- Wuhu Fourth People's Hospital, Wuhu, Anhui, China
| | - Peng Wang
- Wuhu Fourth People's Hospital, Wuhu, Anhui, China
| | - Weidong Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Daizhan Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Yu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Lu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Guang He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
- The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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21
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Giri M, Gupta P, Maulik A, Gracias M, Singh M. Structure and DNA binding analysis of AT-rich interaction domain present in human BAF-B specific subunit BAF250b. Protein Sci 2022; 31:e4294. [PMID: 35481652 PMCID: PMC8994505 DOI: 10.1002/pro.4294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 02/21/2022] [Accepted: 02/28/2022] [Indexed: 11/06/2022]
Abstract
BAF250b and its paralog BAF250a are the DNA-binding central hub proteins present in BAF-B and BAF-A classes of SWI/SNF chromatin-remodeling complexes. BAF250b contains an AT-rich interaction domain (ARID) and C-terminal BAF250_C domain, and it is found mutated in several cancers. ARID is a conserved helix-turn-helix motif-containing DNA-binding domain present in several eukaryotic proteins. The ARID of BAF250b has been proposed to play roles in recruiting SWI/SNF to the target gene promoters for their activation. BAF250b ARID structures had been deposited in the protein data bank by a structural genomics consortium. However, it is not well-studied for its DNA-binding and solution dynamic properties. Here, we report complete backbone NMR resonance assignments of human BAF250b ARID. NMR chemical shifts and the backbone dynamics showed that the solution structure of the protein matched the reported crystal structures. The structure and chemical shift indexing revealed the presence of a short β-sheet in the DNA-binding region of BAF250b ARID that was absent in the structure of its paralog BAF250a ARID. NMR chemical shift perturbations identified DNA-binding residues and revealed the DNA-binding interface on BAF250b ARID. NMR data-driven HADDOCK models of BAF250b ARID - DNA complexes revealed its plausible mode of DNA-binding. Isothermal titration calorimetry experiments showed that BAF250b ARID interacts with DNA sequences with moderate affinities like BAF250a ARID. However, distinct thermodynamic signatures were observed for binding of BAF250a ARID and BAF250b ARID to AT-rich DNA sequence, suggesting that subtle sequence and structural differences in these two proteins influence their DNA-binding.
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Affiliation(s)
- Malyasree Giri
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruIndia
| | - Parul Gupta
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruIndia
| | - Aditi Maulik
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruIndia
| | - Magaly Gracias
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruIndia
| | - Mahavir Singh
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruIndia
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22
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Zhao S, Wu W, Jiang Z, Tang F, Ding L, Xu W, Ruan L. Roles of ARID1A variations in colorectal cancer: a collaborative review. Mol Med 2022; 28:42. [PMID: 35421925 PMCID: PMC9009033 DOI: 10.1186/s10020-022-00469-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/05/2022] [Indexed: 12/24/2022] Open
Abstract
AbstractColorectal cancer (CRC), a common malignancy, is one of the leading cause of cancer death in adults. AT-rich interaction domain 1A (ARID1A), a critical portion of the SWItch/sucrose non-fermentation (SWI/SNF) chromatin remodeling complexes, shows one of the most frequent mutant genes across different human cancer types. Deleterious variations of ARID1A has been recognized to be correlated the tumorigenesis and the poor prognosis of CRC. Here, we summarize recent advances in the clinical implications and molecular pathogenesis of ARID1A variations in CRC. According to independent data of 23 included studies, ARID1A is mutated in 3.6–66.7%. Consistently, all of the 23 relevant studies report that ARID1A functions as a specific tumor suppressor in CRC. Clinically, ARID1A variation status serves as a biomarker for survival prognosis and various therapies for CRC. Mechanistically, the pathophysiologic impacts of ARID1A variations on CRC may be associated with the co-occurrence variations of other genes (i.e., TP53, KRAS, APC, FBXW7, and PIK3CA) and the regulation of several signaling pathways being affected (i.e., WNT signaling, Akt signaling, and MEK/ERK pathway), leading to cell cycle arrest, chromatin remodeling, chromosome organization, and DNA hypermethylation of the cancer cells. The present review highlights ARID1A serving as a potent tumor suppressor and an important prognostic factor in CRC. ARID1A variations hint towards a promising tool for diagnostic tumor profiling and individualized therapeutic targets for CRC in the future.
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23
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Bluemn T, Schmitz J, Zheng Y, Burns R, Zheng S, DeJong J, Christiansen L, Arnold O, Izaguirre-Carbonell J, Wang D, Deshpande AJ, Zhu N. Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis. Leukemia 2022; 36:946-955. [PMID: 35022500 PMCID: PMC10095935 DOI: 10.1038/s41375-021-01505-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 12/16/2021] [Accepted: 12/23/2021] [Indexed: 11/09/2022]
Abstract
The Switch/Sugar Non-Fermenting (SWI/SNF) nucleosome remodeling complexes play important roles in normal development and in the development of various cancers. Core subunits of the SWI/SNF complexes have been shown to have oncogenic roles in acute myeloid leukemia. However, the roles of the unique targeting subunits, including that of Arid2 and Arid1b, in AML leukemogenesis are not well understood. Here, we used conditional knockout mouse models to elucidate their role in MLL-AF9 leukemogenesis. We uncovered that Arid2 has dual roles; enhancing leukemogenesis when deleted during leukemia initiation and yet is required during leukemia maintenance. Whereas, deleting Arid1b in either phase promotes leukemogenesis. Our integrated analyses of transcriptomics and genomic binding data showed that, globally, Arid2 and Arid1b regulate largely distinct sets of genes at different disease stages, respectively, and in comparison, to each other. Amongst the most highly dysregulated transcription factors upon their loss, Arid2 and Arid1b converged on the regulation of Etv4/Etv5, albeit in an opposing manner while also regulating distinct TFs including Gata2,Tcf4, Six4, Irf4 and Hmgn3. Our data demonstrate the differential roles of SWI/SNF subunits in AML leukemogenesis and emphasize that cellular context and disease stage are key in determining their functions during this process.
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Affiliation(s)
- Theresa Bluemn
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jesse Schmitz
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Yongwei Zheng
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Robert Burns
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Shikan Zheng
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Joshua DeJong
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Luke Christiansen
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Olivia Arnold
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Demin Wang
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Aniruddha J Deshpande
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Nan Zhu
- Blood Research Institute, Versiti, Milwaukee, WI, USA.
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
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24
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Korn SM, Schlundt A. Structures and nucleic acid-binding preferences of the eukaryotic ARID domain. Biol Chem 2022; 403:731-747. [PMID: 35119801 DOI: 10.1515/hsz-2021-0404] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/17/2022] [Indexed: 12/28/2022]
Abstract
The DNA-binding AT-rich interactive domain (ARID) exists in a wide range of proteins throughout eukaryotic kingdoms. ARID domain-containing proteins are involved in manifold biological processes, such as transcriptional regulation, cell cycle control and chromatin remodeling. Their individual domain composition allows for a sub-classification within higher mammals. ARID is categorized as binder of double-stranded AT-rich DNA, while recent work has suggested ARIDs as capable of binding other DNA motifs and also recognizing RNA. Despite a broad variability on the primary sequence level, ARIDs show a highly conserved fold, which consists of six α-helices and two loop regions. Interestingly, this minimal core domain is often found extended by helices at the N- and/or C-terminus with potential roles in target specificity and, subsequently function. While high-resolution structural information from various types of ARIDs has accumulated over two decades now, there is limited access to ARID-DNA complex structures. We thus find ourselves left at the beginning of understanding ARID domain target specificities and the role of accompanying domains. Here, we systematically summarize ARID domain conservation and compare the various types with a focus on their structural differences and DNA-binding preferences, including the context of multiple other motifs within ARID domain containing proteins.
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Affiliation(s)
- Sophie Marianne Korn
- Institute for Molecular Biosciences and Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Andreas Schlundt
- Institute for Molecular Biosciences and Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
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25
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Tossetta G, Fantone S, Gesuita R, Montironi R, Marzioni D, Mazzucchelli R. AT-rich interactive domain 1A (ARID1A) cannot be considered a morphological marker for prostate cancer progression: A pilot study. Acta Histochem 2022; 124:151847. [PMID: 35038591 DOI: 10.1016/j.acthis.2022.151847] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/30/2021] [Accepted: 01/10/2022] [Indexed: 12/12/2022]
Abstract
Prostate cancer (PCa) is one of the most common cancers worldwide but it presents many subtypes and patient heterogeneity. It is necessary to discriminate localised not aggressive PCa and metastatic cancer in order to better define the personalised treatment. The identification of an appropriate biomarker to combine with Gleason grading system, that is one of the most important prognostic factors in prostate cancer outcome, remains a major clinical issue. We have tested AT-rich interactive domain 1A (ARID1A) in prostate tissue is order to verify its possible role as morphological marker for prostate cancer progression. ARID1A is a tumour suppressor protein playing a pivotal role in chromatin remodelling during transcriptional regulation. It was decreased in many cancers correlating with tumour aggressiveness. Our data shown that ARID1A had a nuclear staining and that it is significantly decreased in prostate cancers suggesting that it can be involved in this neoplasm but it is not able to discriminate prostate cancer progression.
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26
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Neurobiology of ARID1B haploinsufficiency related to neurodevelopmental and psychiatric disorders. Mol Psychiatry 2022; 27:476-489. [PMID: 33686214 PMCID: PMC8423853 DOI: 10.1038/s41380-021-01060-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 02/04/2021] [Accepted: 02/18/2021] [Indexed: 01/31/2023]
Abstract
ARID1B haploinsufficiency is a frequent cause of intellectual disability (ID) and autism spectrum disorder (ASD), and also leads to emotional disturbances. In this review, we examine past and present clinical and preclinical research into the neurobiological function of ARID1B. The presentation of ARID1B-related disorders (ARID1B-RD) is highly heterogeneous, including varying degrees of ID, ASD, and physical features. Recent research includes the development of suitable clinical readiness assessments for the treatment of ARID1B-RD, as well as similar neurodevelopmental disorders. Recently developed mouse models of Arid1b haploinsufficiency successfully mirror many of the behavioral phenotypes of ASD and ID. These animal models have helped to solidify the molecular mechanisms by which ARID1B regulates brain development and function, including epigenetic regulation of the Pvalb gene and promotion of Wnt/β-catenin signaling in neural progenitors in the ventral telencephalon. Finally, preclinical studies have identified the use of a positive allosteric modulator of the GABAA receptor as an effective treatment for some Arid1b haploinsufficiency-related behavioral phenotypes, and there is potential for the refinement of this therapy in order to translate it into clinical use.
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27
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Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models. Cancers (Basel) 2021; 14:cancers14010071. [PMID: 35008235 PMCID: PMC8750056 DOI: 10.3390/cancers14010071] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful tools to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. In this review, we summarize the main molecular alterations found in pancreatic neoplasms and GEMMs developed based on these alterations. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.
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28
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Caracci MO, Avila ME, Espinoza-Cavieres FA, López HR, Ugarte GD, De Ferrari GV. Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders. Front Mol Neurosci 2021; 14:764756. [PMID: 34858139 PMCID: PMC8632544 DOI: 10.3389/fnmol.2021.764756] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022] Open
Abstract
Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.
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Affiliation(s)
- Mario O. Caracci
- Faculty of Medicine, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
- Faculty of Life Sciences, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
| | - Miguel E. Avila
- Faculty of Veterinary Medicine and Agronomy, Nucleus of Applied Research in Veterinary and Agronomic Sciences (NIAVA), Institute of Natural Sciences, Universidad de Las Américas, Santiago, Chile
| | - Francisca A. Espinoza-Cavieres
- Faculty of Medicine, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
- Faculty of Life Sciences, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
| | - Héctor R. López
- Faculty of Medicine, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
- Faculty of Life Sciences, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
| | - Giorgia D. Ugarte
- Faculty of Medicine, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
- Faculty of Life Sciences, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
| | - Giancarlo V. De Ferrari
- Faculty of Medicine, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
- Faculty of Life Sciences, Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile
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29
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Cheng X, Zhao JX, Dong F, Cao XC. ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target. Front Oncol 2021; 11:759577. [PMID: 34804958 PMCID: PMC8599951 DOI: 10.3389/fonc.2021.759577] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/15/2021] [Indexed: 12/05/2022] Open
Abstract
Distant metastasis is the principal cause of mortality for breast cancer patients. Targeting specific mutations that have been acquired during the evolution process of advanced breast cancer is a potential means of enhancing the clinical efficacy of treatment strategies. In metastatic breast cancer, ARID1A is the most prevalent mutation of the SWI/SNF complex, which regulates DNA repair, recombination, and gene transcription. The low expression of ARID1A is associated with poor disease-free survival and overall survival of patients with luminal A or HER2-rich breast cancer. In addition, ARID1A plays a prominent role in maintaining luminal characteristics and has an advantage for identifying responses to treatment, including endocrine therapies, HDAC inhibitors and CDK4/6 inhibitors. The therapeutic vulnerabilities initiated by ARID1A alterations encourage us to explore new approaches to cope with ARID1A mutant-related drug resistance or metastasis. In this review, we describe the mutation profiles of ARID1A in metastatic breast cancer and the structure and function of ARID1A and the SWI/SNF complex as well as discuss the potential mechanisms of ARID1A-mediated endocrine resistance and therapeutic potential.
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Affiliation(s)
- Xuan Cheng
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Jian-Xiong Zhao
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Feng Dong
- Department of Neurosurgery, Tianjin Medical University General Hospital and Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, Tianjin Medical University, Tianjin, China
| | - Xu-Chen Cao
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
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Sun D, Teng F, Xing P, Li J. ARID1A serves as a receivable biomarker for the resistance to EGFR-TKIs in non-small cell lung cancer. Mol Med 2021; 27:138. [PMID: 34715776 PMCID: PMC8555283 DOI: 10.1186/s10020-021-00400-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/14/2021] [Indexed: 12/15/2022] Open
Abstract
ARID1A is a key component of the SWI/SNF chromatin remodeling complexes which is important for the maintaining of biological processes of cells. Recent studies had uncovered the potential role of ARID1A alterations or expression loss in the therapeutic sensitivity of cancers, but the studies in this field requires to be further summarized and discussed. Therefore, we proposed a series of mechanisms related to the resistance to EGFR-TKIs induced by ARID1A alterations or expression loss and the potential therapeutic strategies to overcome the resistance based on published studies. It suggested that ARID1A alterations or expression loss might be the regulators in PI3K/Akt, JAK/STAT and NF-κB signaling pathways which are strongly associated with the resistance to EGFR-TKIs in NSCLC patients harboring sensitive EGFR mutations. Besides, ARID1A alterations or expression loss could lead to the resistance to EGFR-TKIs via a variety of processes during the tumorigenesis and development of cancers, including epithelial to mesenchymal transition, angiogenesis and the inhibition of apoptosis. Based on the potential mechanisms related to ARID1A, we summarized that the small molecular inhibitors targeting ARID1A or PI3K/Akt pathway, the anti-angiogenic therapy and immune checkpoint inhibitors could be used for the supplementary treatment for EGFR-TKIs among NSCLC patients harboring the concomitant alterations of sensitive EGFR mutations and ARID1A.
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Affiliation(s)
- Dantong Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fei Teng
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Puyuan Xing
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Junling Li
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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31
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Sun D, Zhu Y, Zhao H, Bian T, Li T, Liu K, Feng L, Li H, Hou H. Loss of ARID1A expression promotes lung adenocarcinoma metastasis and predicts a poor prognosis. Cell Oncol (Dordr) 2021; 44:1019-1034. [PMID: 34109546 DOI: 10.1007/s13402-021-00616-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 05/26/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND ARID1A is an essential subunit of SWI/SNF chromatin remodeling complexes. ARID1A gene mutations and loss of ARID1A expression have been observed in a variety of cancers, and to be correlated with invasion, immune escape and synthetic lethality. As yet, however, the biological effect of ARID1A expression and its role in the prognosis of lung adenocarcinoma (LUAD) patients have remained unclear. In this study we aimed to further elucidate the role of ARID1A expression in LUAD in vitro and in vivo and to assess its effect on the clinical prognosis of LUAD patients. METHODS ARID1A expression was detected by IHC in tissue samples from LUAD patients. After regular culturing of LUAD cell lines and constructing stable ARID1A knockdown lines, wound healing and Transwell assays were used to assess the role of ARID1A in cell migration and invasion. The effect of ARID1A knockdown on metastasis was verified in vivo. Western blotting was used to examine the expression of target proteins. Univariate and multivariate analyses were performed to assess survival and to provide variables for nomogram construction. In addition, we used the "rms" package to construct a prognostic nomogram based on a Cox regression model. RESULTS We found that ARID1A expression serves as an effective prognostic marker for LUAD patients. Loss of ARID1A expression correlated with a poor prognosis, as verified with a nomogram based on a Cox regression model. In addition, we found that ARID1A knockdown promoted LUAD cell proliferation, migration and invasion in vitro and enhanced LUAD metastasis in vivo by activating the Akt signaling pathway. CONCLUSIONS Our data indicate that loss of ARID1A expression promotes LUAD metastasis and predicts a poor prognosis in LUAD patients.
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Affiliation(s)
- Dantong Sun
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Shandong, 266000, Qingdao, China
| | - Yan Zhu
- Department of Medical Oncology, The Municipal Hospital of Qingdao, 266000, Qingdao, China
| | - Han Zhao
- Department of Pathology, The Affiliated Hospital of Qingdao University, 266000, Qingdao, China
| | - Tiantian Bian
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao University, 266100, Qingdao, China
| | - Tianjun Li
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Shandong, 266000, Qingdao, China
| | - Kewei Liu
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Shandong, 266000, Qingdao, China
| | - Lizong Feng
- Department of General Surgery, Qingdao Eighth People's Hospital, 266041, Qingdao, China
| | - Hong Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
| | - Helei Hou
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Shandong, 266000, Qingdao, China.
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The BAF chromatin remodeling complexes: structure, function, and synthetic lethalities. Biochem Soc Trans 2021; 49:1489-1503. [PMID: 34431497 DOI: 10.1042/bst20190960] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 02/08/2023]
Abstract
BAF complexes are multi-subunit chromatin remodelers, which have a fundamental role in genomic regulation. Large-scale sequencing efforts have revealed frequent BAF complex mutations in many human diseases, particularly in cancer and neurological disorders. These findings not only underscore the importance of the BAF chromatin remodelers in cellular physiological processes, but urge a more detailed understanding of their structure and molecular action to enable the development of targeted therapeutic approaches for diseases with BAF complex alterations. Here, we review recent progress in understanding the composition, assembly, structure, and function of BAF complexes, and the consequences of their disease-associated mutations. Furthermore, we highlight intra-complex subunit dependencies and synthetic lethal interactions, which have emerged as promising treatment modalities for BAF-related diseases.
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Zhao S, Xu Y, Wu W, Wang P, Wang Y, Jiang H, Zhu J. ARID1A Variations in Cholangiocarcinoma: Clinical Significances and Molecular Mechanisms. Front Oncol 2021; 11:693295. [PMID: 34249744 PMCID: PMC8267411 DOI: 10.3389/fonc.2021.693295] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/03/2021] [Indexed: 01/06/2023] Open
Abstract
Cholangiocarcinoma (CCA), a high mortality malignant carcinoma characterized by advanced disease and frequent recurrence, constitutes a major challenge for treatment and prognosis. AT-rich interaction domain 1A (ARID1A) variation is a distinct genetic entity in CCA, getting mounting concerns recently. Here, we comprehensively reviewed the clinical significance and molecular mechanisms of ARID1A alterations in CCA. Based on the independent data derived from 29 relevant studies, the variation rate of ARID1A in intrahepatic and extrahepatic CCA is reported at 6.9-68.2% and 5-55%, respectively. Most of the included studies (28/29, 96.6%) suggest that ARID1A serves as a tumor suppressor in CCA. ARID1A variation may be an important prognostic indicator to predict disease mortality, metastasis, and recurrence in patients with CCA. Multifactorial molecular mechanisms are involved in the relationship between ARID1A variations and the pathogenesis and pathophysiology of CCA, including disruption of the cell cycle, chromatin remodeling, oxidative stress damage, DNA hypermethylation, and the interaction of multiple genes being affected. This review describes that ARID1A variation might be a potential diagnostic and prognostic biomarker for CCA. Future diagnoses and treatments targeting ARID1A hint towards a precision medicine strategy in the management of CCA.
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Affiliation(s)
- Shankun Zhao
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Youwen Xu
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weizhou Wu
- Department of Urology, Maoming People's Hospital, Maoming, China
| | - Pan Wang
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yichao Wang
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Hao Jiang
- Department of Hepatobiliary Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jie Zhu
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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Odnokoz O, Wavelet-Vermuse C, Hophan SL, Bulun S, Wan Y. ARID1 proteins: from transcriptional and post-translational regulation to carcinogenesis and potential therapeutics. Epigenomics 2021; 13:809-823. [PMID: 33890484 PMCID: PMC8738980 DOI: 10.2217/epi-2020-0414] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
The ARID1 proteins are mutually exclusive subunits of the BRG1/BRM-associated factor (BAF) complexes that play an important role in chromatin remodeling and regulate many fundamental cell functions. The role of ARID1s is well defined as a tumor-suppressive. The cancer cells evolve different mechanisms to downregulate ARID1s and inactivate their functions. ARID1s are frequently mutated in human cancer. The recent findings of ARID1A/B downregulation at transcriptional and translational levels along with their low levels in human cancers indicate the significance of regulatory mechanisms of ARID1s in cancers. In this review, we present the current knowledge on the regulation and alterations of ARID1 protein expression in human cancers and indicate the importance of regulators of ARID1s as a prognostic marker and in potential therapeutic strategies.
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Affiliation(s)
- Olena Odnokoz
- Department of Obstetrics & Gynecology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA,Department of Pharmacology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Cindy Wavelet-Vermuse
- Department of Obstetrics & Gynecology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA,Department of Pharmacology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Shelby L Hophan
- Department of Obstetrics & Gynecology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA,Department of Pharmacology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Serdar Bulun
- Department of Obstetrics & Gynecology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yong Wan
- Department of Obstetrics & Gynecology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA,Department of Pharmacology & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA,Author for correspondence: Tel.: +1 312 503 2769;
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Kato MK, Yoshida H, Tanase Y, Uno M, Ishikawa M, Kato T. Loss of ARID1A Expression as a Favorable Prognostic Factor in Early-Stage Grade 3 Endometrioid Endometrial Carcinoma Patients. Pathol Oncol Res 2021; 27:598550. [PMID: 34257552 PMCID: PMC8262237 DOI: 10.3389/pore.2021.598550] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/12/2021] [Indexed: 11/13/2022]
Abstract
Introduction: High-risk patients with grade 3 endometrioid endometrial carcinoma (G3EEC) who require adjuvant therapy have not been clearly identified. Therefore, the current study aimed to investigate the prognostic impact of ARID1A, p53, and mismatch repair (MMR) protein expressions, previously reported as prognosticators in some gynecological cancers, in patients with early-stage G3EEC. Methods: A total of 67 patients with pathologically confirmed early-stage G3EEC diagnosed between 1997 and 2020 were identified; none received adjuvant chemotherapy. The recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with a log-rank test. The protein expressions of ARID1A, p53, and MMR were examined via immunohistochemistry, and the associations between these biomarkers and clinical outcomes were evaluated. Results: Recurrence was observed in 9 (13%) of the 67 patients with early stage G3EEC. The respective 5-years RFS and OS rates were 87.7% and 93.7%, and 68.6% and 85.7%, respectively for stages I and II. Multivariate analysis showed significantly longer RFS among patients with ARID1A loss (hazard ratio = 8.7; 95% CI, 1.09–69.6, p = 0.04). No significant differences were observed in RFS and OS of patients according to p53 and MMR expression status. Conclusion: ARID1A expression status was a prognosticator for patients with early stage G3EEC without adjuvant therapy, whereas p53 and MMR expression status showed no impact on survival outcomes. ARID1A may become a useful biomarker for stratification of adjuvant treatment for early stage G3EEC patients.
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Affiliation(s)
| | - Hiroshi Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Yasuhito Tanase
- Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan
| | - Masaya Uno
- Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan
| | - Mitsuya Ishikawa
- Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan
| | - Tomoyasu Kato
- Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan
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Moffat JJ, Jung EM, Ka M, Jeon BT, Lee H, Kim WY. Differential roles of ARID1B in excitatory and inhibitory neural progenitors in the developing cortex. Sci Rep 2021; 11:3856. [PMID: 33594090 PMCID: PMC7886865 DOI: 10.1038/s41598-021-82974-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/21/2021] [Indexed: 11/08/2022] Open
Abstract
Genetic evidence indicates that haploinsufficiency of ARID1B causes intellectual disability (ID) and autism spectrum disorder (ASD), but the neural function of ARID1B is largely unknown. Using both conditional and global Arid1b knockout mouse strains, we examined the role of ARID1B in neural progenitors. We detected an overall decrease in the proliferation of cortical and ventral neural progenitors following homozygous deletion of Arid1b, as well as altered cell cycle regulation and increased cell death. Each of these phenotypes was more pronounced in ventral neural progenitors. Furthermore, we observed decreased nuclear localization of β-catenin in Arid1b-deficient neurons. Conditional homozygous deletion of Arid1b in ventral neural progenitors led to pronounced ID- and ASD-like behaviors in mice, whereas the deletion in cortical neural progenitors resulted in minor cognitive deficits. This study suggests an essential role for ARID1B in forebrain neurogenesis and clarifies its more pronounced role in inhibitory neural progenitors. Our findings also provide insights into the pathogenesis of ID and ASD.
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Affiliation(s)
- Jeffrey J Moffat
- Developmental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, 94153, USA
| | - Eui-Man Jung
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Minhan Ka
- Research Center for Substance Abuse Pharmacology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
| | - Byeong Tak Jeon
- Department of Biological Sciences, Kent State University, Kent, OH, 44242, USA
| | - Hyunkyoung Lee
- Department of Biological Sciences, Kent State University, Kent, OH, 44242, USA
| | - Woo-Yang Kim
- Department of Biological Sciences, Kent State University, Kent, OH, 44242, USA.
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Bluemn T, Schmitz J, Chen Y, Zheng Y, Zhang Y, Zheng S, Burns R, DeJong J, Christiansen L, Izaguirre-Carbonell J, Wang D, Zhu N. Arid2 regulates hematopoietic stem cell differentiation in normal hematopoiesis. Exp Hematol 2021; 94:37-46. [PMID: 33346030 PMCID: PMC10041880 DOI: 10.1016/j.exphem.2020.12.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 12/11/2020] [Accepted: 12/13/2020] [Indexed: 01/25/2023]
Abstract
The switch/sugar nonfermenting (SWI/SNF) family of chromatin remodeling complexes have been implicated in normal hematopoiesis. The ARID2 protein is a component of the polybromo-associated BAF (PBAF), one of the two main SWI/SNF complexes. In the current study, we used a conditional Arid2 knockout mouse model to determine its role in normal hematopoiesis. We found that the loss of Arid2 has no discernable effects on steady-state hematopoiesis, with the exception of a modest effect on erythropoiesis. On bone marrow transplantation, however, the loss of Arid2 affects HSC differentiation in a cell-autonomous manner, resulting in significant decreases in the ability to reconstitute the lymphoid lineage. Gene expression analysis of Arid2 knockout cells revealed enrichment of myeloid-biased multipotent progenitor (MPP) cell signatures, while the lymphoid-biased MPPs are enriched in the wild type, consistent with the observed phenotype. Moreover, Arid2 knockout cells revealed enrichment of inflammatory pathways with upregulation of TLR receptors, as well as downstream signaling cascade genes. Furthermore, under lymphocyte-biased growth conditions in vitro, Arid2 null bone marrow cells have significantly impaired proliferation, which decreased further on lipopolysaccharide stimulation. Overall, these data suggest that the loss of Arid2 impairs HSC differentiation ability, and this effect may be mediated through upregulation of inflammatory pathways.
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Affiliation(s)
- Theresa Bluemn
- Blood Research Institute, Versiti, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI
| | | | - Yuhong Chen
- Blood Research Institute, Versiti, Milwaukee, WI
| | | | | | - Shikan Zheng
- Blood Research Institute, Versiti, Milwaukee, WI
| | - Robert Burns
- Blood Research Institute, Versiti, Milwaukee, WI
| | | | - Luke Christiansen
- Blood Research Institute, Versiti, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI
| | | | - Demin Wang
- Blood Research Institute, Versiti, Milwaukee, WI; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Nan Zhu
- Blood Research Institute, Versiti, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI.
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38
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Remodeling of the ARID1A tumor suppressor. Cancer Lett 2020; 491:1-10. [PMID: 32738271 DOI: 10.1016/j.canlet.2020.07.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 07/06/2020] [Accepted: 07/22/2020] [Indexed: 12/26/2022]
Abstract
In recent years, AT-rich interactive domain-containing protein 1A (ARID1A) has been widely accepted as a bona fide tumor suppressor due to its essential role in preventing tumorigenesis and tumor progression in both mouse and human contexts. ARID1A shows high mutation frequencies in both cancers and preneoplastic lesions. The loss of ARID1A expression in cancer cells leads to increases in cell proliferation, invasion and migration and reductions in cell apoptosis and chemosensitivity. The tumor-suppressive role of ARID1A is mainly attributed to its regulation of gene transcription, which can be induced either directly by chromatin remodeling or indirectly by affecting histone modifications. ARID1A also acts independently of its cardinal transcription-regulating mechanisms, which include interfering with protein-protein interactions. Interestingly, nonmutational mechanisms, such as regulation by DNA hypermethylation, microRNAs, and ubiquitinases/deubiquitinases, have provided another perspective on ARID1A inactivation in cancer. Since the critical tumor-suppressive role of ARID1A has been revealed, several studies have attempted to identify synthetic lethal targets with ARID1A mutation/inactivation as an alternative strategy for cancer treatment.
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Reske JJ, Wilson MR, Holladay J, Wegener M, Adams M, Chandler RL. SWI/SNF inactivation in the endometrial epithelium leads to loss of epithelial integrity. Hum Mol Genet 2020; 29:3412-3430. [PMID: 33075803 PMCID: PMC7749707 DOI: 10.1093/hmg/ddaa227] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/01/2020] [Accepted: 10/12/2020] [Indexed: 12/14/2022] Open
Abstract
Although ARID1A mutations are a hallmark feature, mutations in other SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling subunits are also observed in endometrial neoplasms. Here, we interrogated the roles of Brahma/SWI2-related gene 1 (BRG1, SMARCA4), the SWI/SNF catalytic subunit, in the endometrial epithelium. BRG1 loss affects more than one-third of all active genes and highly overlaps with the ARID1A gene regulatory network. Chromatin immunoprecipitation studies revealed widespread subunit-specific differences in transcriptional regulation, as BRG1 promoter interactions are associated with gene activation, while ARID1A binding is associated with gene repression. However, we identified a physiologically relevant subset of BRG1 and ARID1A co-regulated epithelial identity genes. Mice were genetically engineered to inactivate BRG1 specifically in the endometrial epithelium. Endometrial glands were observed embedded in uterine myometrium, indicating adenomyosis-like phenotypes. Molecular similarities were observed between BRG1 and ARID1A mutant endometrial cells in vivo, including loss of epithelial cell adhesion and junction genes. Collectively, these studies illustrate overlapping contributions of multiple SWI/SNF subunit mutations in the translocation of endometrium to distal sites, with loss of cell integrity being a common feature in SWI/SNF mutant endometrial epithelia.
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Affiliation(s)
- Jake J Reske
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Mike R Wilson
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Jeanne Holladay
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Marc Wegener
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Marie Adams
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Ronald L Chandler
- To whom correspondence should be addressed at: Grand Rapids Research Center, 400 Monroe NW, Grand Rapids, MI 49503, USA. Tel: +1 6162340980;
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40
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Sun D, Tian L, Zhu Y, Wo Y, Liu Q, Liu S, Li H, Hou H. Subunits of ARID1 serve as novel biomarkers for the sensitivity to immune checkpoint inhibitors and prognosis of advanced non-small cell lung cancer. Mol Med 2020; 26:78. [PMID: 32791957 PMCID: PMC7425138 DOI: 10.1186/s10020-020-00208-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 08/03/2020] [Indexed: 12/23/2022] Open
Abstract
Introduction Patients with advanced non-small cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Biomarkers such as programmed death-ligand 1 (PD-L1), the tumor mutational burden (TMB) and the mismatch repair (MMR) status are used to predict the prognosis of ICIs therapy. Nevertheless, novel biomarkers need to be further investigated, and a systematic prognostic model is needed for the evaluation of the survival risks of ICIs treatment. Methods A cohort of 240 patients who received ICIs from the cBioPortal for Cancer Genomics was evaluated in this research. Clinical information and targeted sequencing data were acquired for analyses. The Kaplan-Meier plot method was used to perform survival analyses, and selected variables were then confirmed by a novel nomogram constructed by the “rms” package of R software. Results Seven percent of the NSCLC patients harbored ARID1A mutations, while 4% of the NSCLC patients harbored ARID1B mutations. Mutations in ARID1A and ARID1B were confirmed to be associated with sensitivity to ICIs. Patients harboring these mutations were found to have a better response to treatment (ARID1A: P = 0.045; ARID1B: P = 0.034) and prolonged progression-free survival (ARID1B: P = 0.032). Here, a novel nomogram was constructed to predict the prognosis of ICIs treatment. Elevation of the TMB, enhanced expression of PD-L1 and activation of the antigen presentation process and cellular immunity were found to be correlated with ARID1A and ARID1B mutations. Conclusion ARID1A and ARID1B could serve as novel biomarkers for the prognosis and sensitivity to ICIs of advanced NSCLC.
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Affiliation(s)
- Dantong Sun
- Precision Medicine Center of Oncology, the Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266000, Shandong, China
| | - Lu Tian
- College of Environmental Science and Engineering, Ocean University of China, Qingdao, 266100, China
| | - Yan Zhu
- Department of Medical Oncology, the Municipal Hospital of Qingdao, Qingdao, 266000, China
| | - Yang Wo
- Department of Thoracic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Qiaoling Liu
- Department of Medical Oncology, Qingdao West Coast New Area Central Hospital, Qingdao, 266555, China
| | - Shihai Liu
- Medical Animal Laboratory, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Hong Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
| | - Helei Hou
- Precision Medicine Center of Oncology, the Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266000, Shandong, China.
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Arid1b haploinsufficiency in parvalbumin- or somatostatin-expressing interneurons leads to distinct ASD-like and ID-like behavior. Sci Rep 2020; 10:7834. [PMID: 32398858 PMCID: PMC7217886 DOI: 10.1038/s41598-020-64066-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
Inhibitory interneurons are essential for proper brain development and function. Dysfunction of interneurons is implicated in several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID). We have previously shown that Arid1b haploinsufficiency interferes with interneuron development and leads to social, cognitive, and emotional impairments consistent with ASD and ID. It is unclear, however, whether interneurons play a major role for the behavioral deficits in Arid1b haploinsufficiency. Furthermore, it is critical to determine which interneuron subtypes contribute to distinct behavioral phenotypes. In the present study, we generated Arid1b haploinsufficient mice in which a copy of the Arid1b gene is deleted in either parvalbumin (PV) or somatostatin (SST) interneurons, and examined their ASD- and ID-like behaviors. We found that Arid1b haploinsufficiency in PV or SST interneurons resulted in distinct features that do not overlap with one another. Arid1b haploinsufficiency in PV neurons contributed to social and emotional impairments, while the gene deletion in the SST population caused stereotypies as well as learning and memory dysfunction. These findings demonstrate a critical role of interneurons in Arid1b haploinsufficient pathology and suggest that PV and SST interneurons may have distinct roles in modulating neurological phenotypes in Arid1b haploinsufficiency-induced ASD and ID.
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A Caenorhabditis elegans Model for Integrating the Functions of Neuropsychiatric Risk Genes Identifies Components Required for Normal Dendritic Morphology. G3-GENES GENOMES GENETICS 2020; 10:1617-1628. [PMID: 32132169 PMCID: PMC7202017 DOI: 10.1534/g3.119.400925] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Analysis of patient-derived DNA samples has identified hundreds of variants that are likely involved in neuropsychiatric diseases such as autism spectrum disorder (ASD) and schizophrenia (SCZ). While these studies couple behavioral phenotypes to individual genotypes, the number and diversity of candidate genes implicated in these disorders highlights the fact that the mechanistic underpinnings of these disorders are largely unknown. Here, we describe a RNAi-based screening platform that uses C. elegans to screen candidate neuropsychiatric risk genes (NRGs) for roles in controlling dendritic arborization. To benchmark this approach, we queried published lists of NRGs whose variants in ASD and SCZ are predicted to result in complete or partial loss of gene function. We found that a significant fraction (>16%) of these candidate NRGs are essential for dendritic development. Furthermore, these gene sets are enriched for dendritic arbor phenotypes (>14 fold) when compared to control RNAi datasets of over 500 human orthologs. The diversity of PVD structural abnormalities observed in these assays suggests that the functions of diverse NRGs (encoding transcription factors, chromatin remodelers, molecular chaperones and cytoskeleton-related proteins) converge to regulate neuronal morphology and that individual NRGs may play distinct roles in dendritic branching. We also demonstrate that the experimental value of this platform by providing additional insights into the molecular frameworks of candidate NRGs. Specifically, we show that ANK2/UNC-44 function is directly integrated with known regulators of dendritic arborization and suggest that altering the dosage of ARID1B/LET-526 expression during development affects neuronal morphology without diminishing aspects of cell fate specification.
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43
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Golyan FF, Druley TE, Abbaszadegan MR. Whole-exome sequencing of familial esophageal squamous cell carcinoma identified rare pathogenic variants in new predisposition genes. Clin Transl Oncol 2020; 22:681-693. [PMID: 31321674 DOI: 10.1007/s12094-019-02174-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/28/2019] [Indexed: 11/26/2022]
Abstract
PURPOSE Esophageal squamous cell carcinoma (ESCC) is one of the most important causes of mortality in the developing world. Although hereditary forms arise from germ-line mutations in TP53, Rb, and the mismatch repair genes, many familial cases present with an unknown inherited cause. The new theory of rare, high-penetrance mutations in less known genes is a likely explanation for the underlying predisposition in some of these familial cases. METHODS Exome sequencing was performed in 9 patients with esophageal squamous cancer from 9 families with strong disease aggregation without mutations in known hereditary esophageal cancer genes. Data analysis was limited to only really rare variants (0-0.01%), producing a putative loss of function and located in genes with a role compatible with carcinogenesis. RESULTS Twenty-two final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDK11A, ARID1A, JMJD6, MAML3, CDKN2AIP, and PHLDA1. CONCLUSION Together, we identified new potential esophageal squamous cancer predisposition variants in genes which may have a role in cancer and are involved in chromatin remodeling and cell-cycle pathway, which could increase the risk of ESCC.
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Affiliation(s)
- F F Golyan
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - T E Druley
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - M R Abbaszadegan
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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44
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Coffin-Siris Syndrome-1: Report of five cases from Asian populations with truncating mutations in the ARID1B gene. J Neurol Sci 2020; 414:116819. [PMID: 32339967 DOI: 10.1016/j.jns.2020.116819] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND Pathogenic variants of the ARID1B gene are recognized as the most common cause of Coffin-Siris syndrome (CSS) and also one of the most common causes for intellectual disability (ID). Reported ARID1B variants in association with CSS are mostly from patients of European ancestry. METHODS We performed next-generation sequencing to identify pathogenic variants in patients with congenital disorders from the Genetics clinics. The identified variants were validated by Sanger sequencing. Parental samples were tested by Sanger sequencing to determine inheritance status. RESULTS Truncating variants in ARID1B were identified in five unrelated Asian patients (one Malay, two Chinese and two Indian) with features of CSS. One was a nonsense mutation which had been documented in three other reports while the other four were novel variants, including two nonsense substitutions and two small deletions resulting in premature termination of translation. Similar to previous reports, all patients have developmental and speech delay, with additional presentations such as ectodermal/facial abnormalities commonly observed in CSS patients. CONCLUSIONS Our results unveil ARID1B variants in association with CSS in multiple Southeast Asian ethnic groups, and confirm that variants associated with this disorder tend to be of the truncating type. This finding may provide additional insight into the function of the protein and the disease mechanism.
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45
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Mohd Yunos RI, Ab Mutalib NS, Tieng FYF, Abu N, Jamal R. Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine. Biomolecules 2020; 10:biom10030476. [PMID: 32245111 PMCID: PMC7175115 DOI: 10.3390/biom10030476] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023] Open
Abstract
Global statistics have placed colorectal cancer (CRC) as the third most frequently diagnosed cancer and the fourth principal cause of cancer-related deaths worldwide. Improving survival for CRC is as important as early detection. Personalized medicine is important in maximizing an individual's treatment success and minimizing the risk of adverse reactions. Approaches in achieving personalized therapy in CRC have included analyses of specific genes with its clinical implications. Tumour genotyping via next-generation sequencing has become a standard practice to guide clinicians into predicting tumor behaviour, disease prognosis, and treatment response. Nevertheless, better prognostic markers are necessary to further stratify patients for personalized treatment plans. The discovery of new markers remains indispensable in providing the most effective chemotherapy in order to improve the outcomes of treatment and survival in CRC patients. This review aims to compile and discuss newly discovered, less frequently mutated genes in CRC. We also discuss how these mutations are being used to assist therapeutic decisions and their potential prospective clinical utilities. In addition, we will summarize the importance of profiling the large genomic rearrangements, gene amplification, and large deletions and how these alterations may assist in determining the best treatment option for CRC patients.
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Affiliation(s)
| | | | | | | | - Rahman Jamal
- Correspondence: (N.S.A.M.); (R.J.); Tel.: +60-3-91459073 (N.S.A.M.); +60-3-91459000 (R.J.)
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46
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Giri M, Maulik A, Singh M. Signatures of Specific DNA Binding by the AT-Rich Interaction Domain of BAF250a. Biochemistry 2019; 59:100-113. [PMID: 31825600 DOI: 10.1021/acs.biochem.9b00852] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The AT-rich interaction domain (ARID) containing BAF250a is a subunit of the BAF-A class of SWI/SNF chromatin remodeling complexes. The ARID belongs to a family of conserved DNA binding domains found in several eukaryotic proteins; however, its exact contribution to BAF250a function and the mechanism of its DNA binding are not well understood. Here we have probed the interaction of the BAF250a ARID with three different double-stranded DNA (dsDNA) sequences to understand its DNA binding properties. A comprehensive biophysical and thermodynamic study using nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry revealed the complex nature of BAF250a ARID-DNA interactions. The thermodynamic signatures of the BAF250a ARID with 12 A-T bp dsDNA (AT-12) are distinct from those of 12 G-C bp dsDNA (GC-12) or 12 bp Dickerson dodecamer DNA (DD-12) sequences. We observed that the binding of the BAF250a ARID with AT-12 DNA is enthalpically driven in a tested temperature range of 5-25 °C. BAF250a ARID/AT-12 DNA interaction exhibited a larger negative calorimetric specific heat change (ΔCp) compared to that of BAF250a ARID/GC-12 DNA or BAF250a ARID/DD-12 DNA interactions. In the presence of salt (NaCl), ARID/AT-12 DNA binding was less perturbed than ARID/GC-12 DNA or ARID/DD-12 DNA binding. Overall, these results show that BAF250a ARID/AT-12 DNA interaction has signatures of "specific" binding. Furthermore, using NMR chemical shift perturbation experiments, we have identified DNA binding residues on the BAF250a ARID and generated a data-driven HADDOCK model of the ARID/DNA complex that was further supported by mutating key lysine residues that were found to be important for DNA binding.
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Affiliation(s)
- Malyasree Giri
- Molecular Biophysics Unit , Indian Institute of Science , Bengaluru 560012 , India
| | - Aditi Maulik
- Molecular Biophysics Unit , Indian Institute of Science , Bengaluru 560012 , India
| | - Mahavir Singh
- Molecular Biophysics Unit , Indian Institute of Science , Bengaluru 560012 , India.,NMR Research Centre , Indian Institute of Science , Bengaluru 560012 , India
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Ribeiro ML, Reyes-Garau D, Armengol M, Fernández-Serrano M, Roué G. Recent Advances in the Targeting of Epigenetic Regulators in B-Cell Non-Hodgkin Lymphoma. Front Genet 2019; 10:986. [PMID: 31681423 PMCID: PMC6807552 DOI: 10.3389/fgene.2019.00986] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022] Open
Abstract
In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field.
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Affiliation(s)
- Marcelo L. Ribeiro
- Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University Medical School, Braganca Paulista, São Paulo, Brazil
| | - Diana Reyes-Garau
- Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
| | - Marc Armengol
- Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
| | - Miranda Fernández-Serrano
- Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
| | - Gaël Roué
- Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
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Xu H, Zhao X, Bhojwani D, E S, Goodings C, Zhang H, Seibel NL, Yang W, Li C, Carroll WL, Evans WE, Yang JJ. ARID5B Influences Antimetabolite Drug Sensitivity and Prognosis of Acute Lymphoblastic Leukemia. Clin Cancer Res 2019; 26:256-264. [PMID: 31573954 DOI: 10.1158/1078-0432.ccr-19-0190] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 06/13/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE Treatment outcomes for childhood acute lymphoblastic leukemia (ALL) have improved steadily, but a significant proportion of patients still experience relapse due to drug resistance, which is partly explained by inherited and/or somatic genetic alternations. Recently, we and others have identified genetic variants in the ARID5B gene associated with susceptibility to ALL and also with relapse. In this study, we sought to characterize the molecular pathway by which ARID5B affects antileukemic drug response in patients with ALL. EXPERIMENTAL DESIGN We analyzed association of ARID5B expression in primary human ALL blasts with molecular subtypes and treatment outcome. Subsequent mechanistic studies were performed in ALL cell lines by manipulating ARID5B expression isogenically, in which we evaluated drug sensitivity, metabolism, and molecular signaling events. RESULTS ARID5B expression varied substantially by ALL subtype, with the highest level being observed in hyperdiploid ALL. Lower ARID5B expression at diagnosis was associated with the risk of ALL relapse, and further reduction was noted at ALL relapse. In isogenic ALL cell models in vitro, ARID5B knockdown led to resistance specific to antimetabolite drugs (i.e., 6-mercaptopurine and methotrexate), without significantly affecting sensitivity to other antileukemic agents. ARID5B downregulation significantly inhibited ALL cell proliferation and caused partial cell-cycle arrest. At the molecular level, the cell-cycle checkpoint regulator p21 (encoded by CDKN1A) was most consistently modulated by ARID5B, plausibly as its direct transcription regulation target. CONCLUSIONS Our data indicate that ARID5B is an important molecular determinant of antimetabolite drug sensitivity in ALL, in part, through p21-mediated effects on cell-cycle progression.
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Affiliation(s)
- Heng Xu
- Department of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xujie Zhao
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Deepa Bhojwani
- Division of Hematology, Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, California
| | - Shuyu E
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Charnise Goodings
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Hui Zhang
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.,Department of Pediatric Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China
| | - Nita L Seibel
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland
| | - Wentao Yang
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Chunliang Li
- Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - William L Carroll
- Departments of Pediatrics and Pathology, New York University Langone Medical Center, New York, New York
| | - William E Evans
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.,Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Jun J Yang
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee. .,Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee
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Kishida Y, Oishi T, Sugino T, Shiomi A, Urakami K, Kusuhara M, Yamaguchi K, Kitagawa Y, Ono H. Associations Between Loss of ARID1A Expression and Clinicopathologic and Genetic Variables in T1 Early Colorectal Cancer. Am J Clin Pathol 2019; 152:463-470. [PMID: 31263894 DOI: 10.1093/ajcp/aqz062] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES To evaluate the relationships between adenine-thymine-rich interactive domain 1A (ARID1A) expression and the clinicopathologic features in T1 colorectal cancer (CRC) and to investigate whether the presence of ARID1A protein is related to genetic changes. METHODS We retrospectively studied 219 surgically resected T1 CRCs. ARID1A expression was assessed by immunohistochemical methods, and the correlation between ARID1A expression and clinicopathologic features was evaluated. The relationship between ARID1A expression and 409 cancer-related gene mutations was also evaluated using next-generation sequencing (NGS). RESULTS Immunohistochemical staining indicated negative ARID1A expression in 4.6%. Loss of ARID1A expression was significantly associated with younger age, lymphatic invasion, and lymph node metastasis (LNM). NGS showed that PKHD1, RNF213, and MSH6 mutations were more frequent in ARID1A-negative tumors, whereas KRAS mutations were more common in ARID1A-positive tumors. CONCLUSIONS In T1 CRC, negative ARID1A expression was correlated with early onset, lymphatic invasion, and LNM. Mutations in some cancer-related genes were possibly related with ARID1A expression.
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Affiliation(s)
- Yoshihiro Kishida
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Takuma Oishi
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Akio Shiomi
- Division of Colorectal Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Masatoshi Kusuhara
- Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
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50
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Abstract
Renal cell carcinomas (RCCs) are a diverse set of malignancies that have recently been shown to harbour mutations in a number of chromatin modifier genes - including PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2 - through high-throughput sequencing efforts. Current research focuses on understanding the biological activities that chromatin modifiers employ to suppress tumorigenesis and on developing clinical approaches that take advantage of this knowledge. Unsurprisingly, several common themes unify the functions of these epigenetic modifiers, particularly regulation of histone post-translational modifications and nucleosome organization. Furthermore, chromatin modifiers also govern processes crucial for DNA repair and maintenance of genomic integrity as well as the regulation of splicing and other key processes. Many chromatin modifiers have additional non-canonical roles in cytoskeletal regulation, which further contribute to genomic stability, expanding the repertoire of functions that might be essential in tumorigenesis. Our understanding of how mutations in chromatin modifiers contribute to tumorigenesis in RCC is improving but remains an area of intense investigation. Importantly, elucidating the activities of chromatin modifiers offers intriguing opportunities for the development of new therapeutic interventions in RCC.
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Affiliation(s)
- Aguirre A de Cubas
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - W Kimryn Rathmell
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
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