|
1
|
Casamassimi A, Rienzo M, Di Zazzo E, Sorrentino A, Fiore D, Proto MC, Moncharmont B, Gazzerro P, Bifulco M, Abbondanza C. Multifaceted Role of PRDM Proteins in Human Cancer. Int J Mol Sci 2020; 21:ijms21072648. [PMID: 32290321 PMCID: PMC7177584 DOI: 10.3390/ijms21072648] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/29/2020] [Accepted: 04/08/2020] [Indexed: 12/15/2022] Open
Abstract
The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.
Collapse
Affiliation(s)
- Amelia Casamassimi
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
- Correspondence: (A.C.); (C.A.); Tel.: +39-081-566-7579 (A.C.); +39-081-566-7568 (C.A.)
| | - Monica Rienzo
- Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy;
| | - Erika Di Zazzo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy;
| | - Anna Sorrentino
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
| | - Donatella Fiore
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy; (D.F.); (M.C.P.); (P.G.)
| | - Maria Chiara Proto
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy; (D.F.); (M.C.P.); (P.G.)
| | - Bruno Moncharmont
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy;
| | - Patrizia Gazzerro
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy; (D.F.); (M.C.P.); (P.G.)
| | - Maurizio Bifulco
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy;
| | - Ciro Abbondanza
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
- Correspondence: (A.C.); (C.A.); Tel.: +39-081-566-7579 (A.C.); +39-081-566-7568 (C.A.)
| |
Collapse
|
|
2
|
Zavadil JA, Herzig MCS, Hildreth K, Foroushani A, Boswell W, Walter R, Reddick R, White H, Zare H, Walter CA. C3HeB/FeJ Mice mimic many aspects of gene expression and pathobiological features of human hepatocellular carcinoma. Mol Carcinog 2018; 58:309-320. [PMID: 30365185 DOI: 10.1002/mc.22929] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/23/2018] [Indexed: 12/18/2022]
Abstract
Hepatocellular carcinoma (HCC) remains a deadly cancer, underscoring the need for relevant preclinical models. Male C3HeB/FeJ mice model spontaneous HCC with some hepatocarcinogenesis susceptibility loci corresponding to syntenic regions of human chromosomes altered in HCC. We tested other properties of C3HeB/FeJ tumors for similarity to human HCC. C3HeB/FeJ tumors were grossly visible at 4 months of age, with prevalence and size increasing until about 11 months of age. Histologic features shared with human HCC include hepatosteatosis, tumor progression from dysplasia to poorly differentiated, vascular invasion, and trabecular, oncocytic, vacuolar, and clear cell variants. More tumor cells displayed cytoplasmic APE1 staining versus normal liver. Ultrasound effectively detected and monitored tumors, with 85.7% sensitivity. Over 5000 genes were differentially expressed based on the GSE62232 and GSE63898 human HCC datasets. Of these, 158 and 198 genes, respectively, were also differentially expressed in C3HeB/FeJ. Common cancer pathways, cell cycle, p53 signaling and other molecular aspects, were shared between human and mouse differentially expressed genes. We established eigengenes that distinguish HCC from normal liver in the C3HeB/FeJ model and a subset of human HCC. These features extend the relevance and improve the utility of the C3HeB/FeJ line for HCC studies.
Collapse
Affiliation(s)
- Jessica A Zavadil
- Department of Cell Systems & Anatomy, University of Texas Health Science Center, San Antonio, Texas
| | - Maryanne C S Herzig
- Department of Cell Systems & Anatomy, University of Texas Health Science Center, San Antonio, Texas
| | - Kim Hildreth
- Department of Cell Systems & Anatomy, University of Texas Health Science Center, San Antonio, Texas
| | - Amir Foroushani
- Department of Computer Science, Texas State University, San Marcos, Texas
| | - William Boswell
- Chemistry & Biochemistry Department, Texas State University, San Marcos, Texas
| | - Ronald Walter
- Chemistry & Biochemistry Department, Texas State University, San Marcos, Texas
| | - Robert Reddick
- Pathology Department, University of Texas Health Science Center, San Antonio, Texas
| | - Hugh White
- Radiology Department, University of Texas Health Science Center, San Antonio, Texas.,Radiology Department, Audie L. Murphy Memorial Veterans Affairs Hospital, San Antonio, Texas
| | - Habil Zare
- Department of Cell Systems & Anatomy, University of Texas Health Science Center, San Antonio, Texas
| | - Christi A Walter
- Department of Cell Systems & Anatomy, University of Texas Health Science Center, San Antonio, Texas
| |
Collapse
|
|
3
|
Sorrentino A, Rienzo M, Ciccodicola A, Casamassimi A, Abbondanza C. Human PRDM2: Structure, function and pathophysiology. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2018; 1861:S1874-9399(18)30071-3. [PMID: 29883756 DOI: 10.1016/j.bbagrm.2018.06.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 12/22/2022]
Abstract
PRDM2/RIZ is a member of a superfamily of histone/protein methyltransferases (PRDMs), which are characterized by the conserved N-terminal PR domain, with methyltransferase activity and zinc finger arrays at the C-terminus. Similar to other family members, two main protein types, known as RIZ1 and RIZ2, are produced from the PRDM2 locus differing by the presence or absence of the PR domain. The imbalance in their respective amounts may be an important cause of malignancy, with the PR-positive isoform commonly lost or downregulated and the PR-negative isoform always being present at higher levels in cancer cells. Interestingly, the RIZ1 isoform also represents an important target of estradiol action downstream of the interaction with hormone receptor. Furthermore, the imbalance between the two products could also be a molecular basis for other human diseases. Thus, understanding the molecular mechanisms underlying PRDM2 function could be useful in the pathophysiological context, with a potential to exploit this information in clinical practice.
Collapse
Affiliation(s)
- A Sorrentino
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy; Department of Science and Technology, University of Naples "Parthenope", Naples, Italy
| | - M Rienzo
- Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - A Ciccodicola
- Department of Science and Technology, University of Naples "Parthenope", Naples, Italy; Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy
| | - A Casamassimi
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - C Abbondanza
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
| |
Collapse
|
|
4
|
RIZ1 is regulated by estrogen and suppresses tumor progression in endometrial cancer. Biochem Biophys Res Commun 2017; 489:96-102. [PMID: 28528974 DOI: 10.1016/j.bbrc.2017.05.095] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 05/17/2017] [Indexed: 11/22/2022]
Abstract
Endometrial cancer (EC) is the estrogen-dependent gynecologic malignancy, however the molecular mechanism involved in the development and progression of EC remain unclear. The aim of this study was to investigate the role of RIZ1 in EC. Immunohistochemical analysis revealed that RIZ1was decreased in EC than in normal endometrium. Lower RIZ1 level was correlated with high-grade carcinoma (p = 0.048) and positive expression of ERα (p = 0.004). In EC cells, estrogen could down regulated the expression of RIZ1, however, ICI182,780 could up regulated the expression of RIZ1. Besides, in vitro and in vivo, RIZ1 could remarkably suppress tumor proliferation, metastasis and invasion. Our data support that RIZ1 was a novel tumor suppressor and could provide a potential therapeutic target in human EC.
Collapse
|
|
5
|
Critical Function of PRDM2 in the Neoplastic Growth of Testicular Germ Cell Tumors. BIOLOGY 2016; 5:biology5040054. [PMID: 27983647 PMCID: PMC5192434 DOI: 10.3390/biology5040054] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/14/2016] [Accepted: 12/05/2016] [Indexed: 12/30/2022]
Abstract
Testicular germ cell tumors (TGCTs) derive from primordial germ cells. Their maturation is blocked at different stages, reflecting histological tumor subtypes. A common genetic alteration in TGCT is a deletion of the chromosome 1 short arm, where the PRDM2 gene, belonging to the Positive Regulatory domain gene (PRDM) family, is located. Expression of PRDM2 gene is shifted in different human tumors, where the expression of the two principal protein forms coded by PRDM2 gene, RIZ1 and RIZ2, is frequently unbalanced. Therefore, PRDM2 is actually considered a candidate tumor suppressor gene in different types of cancer. Although recent studies have demonstrated that PRDM gene family members have a pivotal role during the early stages of testicular development, no information are actually available on the involvement of these genes in TGCTs. In this article we show by qRT-PCR analysis that PRDM2 expression level is modulated by proliferation and differentiation agents such as estradiol, whose exposure during fetal life is probably an important risk factor for TGCTs development in adulthood. Furthermore in normal and cancer germ cell lines, PRDM2 binds estradiol receptor α (ERα) and influences proliferation, survival and apoptosis, as previously reported using MCF-7 breast cancer cell line, suggesting a potential tumor-suppressor role in TGCT formation.
Collapse
|
|
6
|
Mir R, Najar IA, Guru S, Javaid J, Yadav P, Masroor M, Zuberi M, Farooq S, Bhat M, Gupta N, Ray PC, Saxena A. A deletion polymorphism in the RIZ gene is associated with increased progression of imatinib treated chronic myeloid leukemia patients. Leuk Lymphoma 2016; 58:1694-1701. [PMID: 27830966 DOI: 10.1080/10428194.2016.1251589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
RIZ1 encodes a retinoblastoma (Rb)-interacting zinc finger protein, is commonly lost or expressed at reduced levels in cancer cells. The RIZ1 gene locus commonly undergoes LOH in many cancers. Here, we analyzed Proline insertion-deletion polymorphism at amino acid position 704 in the RIZ1 gene and its association with CML. The RIZ1 pro-704 LOH genotypes were determined by AS-PCR in 100 CML patients among which 50 were in CP-CML, 25 in AP-CML, and 25 in BC-CML. Pro704 ins/del polymorphism (LOH) was detected in 27% CML patients. Proline ins-ins homozygosity, del-del homozygosity and ins-del heterozygosity was detected in 9%, 18%, and 73% CML patients compared with 3%, 3%, and 94% in healthy controls, respectively (p < .0003). A four-fold increased risk was found to be associated del-del genotype. We found a statistically significant association between RIZ1 LOH and stage (p > .01) and hematological resistance (p > .001). However, there were no correlations found with other clinical parameters like age, gender, thrombocytopia, type of BCR-ABL, and molecular response. Our findings suggest that proline 704 del-del homozygosity phenotype can play an important role in progression of CML.
Collapse
Affiliation(s)
- Rashid Mir
- a Prince Fahd Bin Sultan Research Chair, Cancer Molecular Genetics, Faculty of Applied Medical Sciences , University of Tabuk , Tabuk , Saudi Arabia
| | - Imtiyaz Ah Najar
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Sameer Guru
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Jamsheed Javaid
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Prasant Yadav
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Mirza Masroor
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Mariyam Zuberi
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Shazia Farooq
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Musadiq Bhat
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Naresh Gupta
- c Department of Medicine , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Prakash Chander Ray
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| | - Alpana Saxena
- b Department of Biochemistry , Maulana Azad Medical College and Associated Hospitals , New Delhi , India
| |
Collapse
|
|
7
|
Chen QW, Zhu XY, Li YY, Meng ZQ. Epigenetic regulation and cancer (review). Oncol Rep 2013; 31:523-32. [PMID: 24337819 DOI: 10.3892/or.2013.2913] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 09/04/2013] [Indexed: 11/06/2022] Open
Abstract
'Epigenetics' is defined as the inheritable changes in gene expression with no alterations in DNA sequences. Epigenetics is a rapidly expanding field, and the study of epigenetic regulation in cancer is emerging. Disruption of the epigenome is a fundamental mechanism in cancer, and several epigenetic drugs have been proven to prolong survival and to be less toxic than conventional chemotherapy. Promising results from combination clinical trials with DNA methylation inhibitors and histone deacetylase inhibitors have recently been reported, and data are emerging that describe molecular determinants of clinical responses. Despite significant advances, challenges remain, including a lack of predictive markers, unclear mechanisms of response and resistance, and rare responses in solid tumors. Preclinical studies are ongoing with novel classes of agents that target various components of the epigenetic machinery. In the present review, examples of studies that demonstrate the role of epigenetic regulation in human cancers with the focus on histone modifications and DNA methylation, and the recent clinical and translational data in the epigenetics field that have potential in cancer therapy are discussed.
Collapse
Affiliation(s)
- Q W Chen
- Department of Integrated Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - X Y Zhu
- Department of Integrated Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Y Y Li
- Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Z Q Meng
- Department of Integrated Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| |
Collapse
|
|
8
|
Dong SW, Li D, Xu C, Sun P, Wang YG, Zhang P. Alteration in gene expression profile and oncogenicity of esophageal squamous cell carcinoma by RIZ1 upregulation. World J Gastroenterol 2013; 19:6170-6177. [PMID: 24115813 PMCID: PMC3787346 DOI: 10.3748/wjg.v19.i37.6170] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 07/23/2013] [Accepted: 08/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) upregulation in gene expression profile and oncogenicity of human esophageal squamous cell carcinoma (ESCC) cell line TE13.
METHODS: TE13 cells were transfected with pcDNA3.1(+)/RIZ1 and pcDNA3.1(+). Changes in gene expression profile were screened and the microarray results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Nude mice were inoculated with TE13 cells to establish ESCC xenografts. After two weeks, the inoculated mice were randomly divided into three groups. Tumors were injected with normal saline, transfection reagent pcDNA3.1(+) and transfection reagent pcDNA3.1(+)/RIZ1, respectively. Tumor development was quantified, and changes in gene expression of RIZ1 transfected tumors were detected by RT-PCR and Western blotting.
RESULTS: DNA microarray data showed that RIZ1 transfection induced widespread changes in gene expression profile of cell line TE13, with 960 genes upregulated and 1163 downregulated. Treatment of tumor xenografts with RIZ1 recombinant plasmid significantly inhibited tumor growth, decreased tumor size, and increased expression of RIZ1 mRNA compared to control groups. The changes in gene expression profile were also observed in vivo after RIZ1 transfection. Most of the differentially expressed genes were associated with cell development, supervision of viral replication, lymphocyte costimulatory and immune system development in esophageal cells. RIZ1 gene may be involved in multiple cancer pathways, such as cytokine receptor interaction and transforming growth factor beta signaling.
CONCLUSION: The development and progression of esophageal cancer are related to the inactivation of RIZ1. Virus infection may also be an important factor.
Collapse
|
|
9
|
Dong SW, Zhang P, Liu YM, Cui YT, Wang S, Liang SJ, He Z, Sun P, Wang YG. Study on RIZ1 gene promoter methylation status in human esophageal squamous cell carcinoma. World J Gastroenterol 2012; 18:576-82. [PMID: 22363126 PMCID: PMC3280405 DOI: 10.3748/wjg.v18.i6.576] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 07/09/2011] [Accepted: 11/09/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the promoter region methylation status of retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) in the human esophageal squamous cell carcinoma (ESCC) cell lines and tissues and verify the relationship between methylation of RIZ1 and oncogenesis, tumor progression and metastasis etc of ESCC.
METHODS: Methylation-specific polymerase chain reaction (MSP) was used to investigate the promoter region methylation status of RIZ1 in 6 ESCC cell lines. One cell line where RIZ1 promoter region methylation was detected was selected for the next study, where the cell line was treated with 5-aza-CdR. Real-time polymerase chain reaction was used to investigate its influence on the transcription of RIZ1. Experiments using frozen pathological specimens from 47 ESCC patients were performed using the same MSP methodology.
RESULTS: Promoter methylation of RIZ1 gene was detected in TE13, CaEs17 and EC109 cell lines and the cell line TE13 was chosen for further study. The expression of RIZ1 mRNA in TE-13 was up-regulated after treatment with 5-aza-CdR. The rate of methylation in carcinomas tissues was significantly higher than those in matched neighboring normal and distal ending normal tissue, and the deviation of data was statistically significant (χ2 = 24.136, P < 0.01). Analysis of the gender, age familial history, tumour deviation, tumour saturation, lymph gland displacement and clinical staging of 47 samples from ESCC patients showed that the fluctuation of data was not statistically significant.
CONCLUSION: Promoter methylation may play an important role in the epigenetic silencing of RIZ1 gene expression in human ESCC. RIZ1 is considered to be a potential tumor suppressor gene and may be a biological parameter for testing early stage human ESCC.
Collapse
|
|
10
|
Abstract
Cancer disparities in incidence and death rates exist among various racial and ethnic groups. These disparities are thought to be due to socioeconomic status, culture, diet, stress, the environment, and biology. Biological functions, such as epigenetic processes, are affected by all these causal factors and extend throughout the life course. Epigenetic processes, in particular DNA methylation, may play a role in the induction of phenotypes with increased cancer risk due to exposure to these multiple factors. DNA methylation is known to cause changes in gene expression of key regulatory genes in cancer. There are limited studies in which epigenetic changes have been explored to address cancer disparities in various racial and ethnic populations. These few studies have reported significant epigenetic differences in various racial and ethnic groups that could account for the differences seen in tumor initiation, progression, aggressiveness, and outcome of these cancers. Genes differentially methylated among these racially and ethnically diverse populations were involved in important cellular functions, such as tumor growth, tumor suppression, hormone receptors, and genes involved in tumor metastasis. Epigenetic research with the advancement in technology has helped identify biomarkers, therapeutic targets, and understand cancer causation in the general population. Unfortunately, these advances in technology have not been applied to explore the basis for cancer health disparities. More research in epigenetics is needed that will enhance our understanding of the determinants of cancer across various diverse populations and ultimately reduce cancer health disparities.
Collapse
Affiliation(s)
- Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
| | | | | |
Collapse
|
|
11
|
Yu J, Wang YJ, Gao YT, Shi WX, Wang QH, Liu T, Xu YJ, Yang B, Du Z. Detection of HCC-associated gene expression by real-time fluorescence quantitative PCR to establish a molecular diagnostic index for HCC. Shijie Huaren Xiaohua Zazhi 2011; 19:588-595. [DOI: 10.11569/wcjd.v19.i6.588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a molecular diagnostic index for hepatocellular carcinoma (HCC).
METHODS: The expression of 11 genes was assessed by real-time fluorescent quantitative polymerase chain reaction (QRT-PCR) in 40 HCC specimens and matched tumor-adjacent specimens and surgical margin specimens, 10 cirrhotic tissue specimens, and 10 normal liver tissue specimens. Using G3PDH as a control, the 2-ΔΔCT method was used to calculate the relative gene expression levels. HCC-associated genes were then selected to establish a molecular diagnostic model for HCC.
RESULTS: Compared with normal liver tissue specimens, approximately 65.0%, 75.0%, and 67.5% of HCC specimens showed a >3-fold increase in the expression levels of tumor suppressor genes PRDM2, IGFBP3, and DLC-1, and approximately 87.5%, 77.5%, 82.5%, 85.0%, and 67.5% of HCC specimens showed a >3-fold decrease in the expression levels of oncogenes GPC3, STMN, CCNA2, BIRC5, and AFP, respectively. The expression levels of these eight genes differed significantly between HCC and cirrhotic tissue (0.45 ± 0.69 vs 0.50 ± 0.20; 0.17 ± 0.20 vs 0.67 ± 0.47; 0.29 ± 0.48 vs 0.58 ± 0.60; 677.57 ± 999.30 vs 4.41 ± 3.99; 17.56 ± 28.28 vs 1.17 ± 1.08; 53.17 ± 103.64 vs 2.09 ± 1.50; 16.53 ± 16.39 vs 1.82 ± 1.39; 4445.70 ± 11642.87 vs 0.86 ± 0.43, all P < 0.05). Molecular diagnostic index was estimated based on these eight genes, which was 2.2 ± 1.5, 3.0 ± 1.6, 2.9 ± 1.5, 6.3 ± 1.2 for liver cirrhosis, surgical margin, tumor-adjacent tissue, and cancer tissue, respectively. The molecular diagnostic index for cancer tissue was significantly different from those for liver cirrhosis, surgical margin, and tumor-adjacent tissue. When a molecular diagnostic index of 4 or greater was adopted to diagnose liver cancer using liver cirrhosis as a control, the sensitivity, specificity, and the area under the receiving operative curve (ROC) were 100%, 90%, and 0.995, respectively.
CONCLUSION: A molecular diagnostic index for HCC was successfully established using fluorescence quantitative PCR to detect HCC-associated genes.
Collapse
|
|
12
|
Zhang C, Li H, Wang Y, Liu W, Zhang Q, Zhang T, Zhang X, Han B, Zhou G. Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications. J Hepatol 2010; 53:889-95. [PMID: 20675009 DOI: 10.1016/j.jhep.2010.05.012] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2009] [Revised: 04/20/2010] [Accepted: 05/10/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The retinoblastoma-interacting zinc finger gene RIZ1 is inactivated in many cancers, but the underlying mechanisms remain unknown. This study aimed to investigate the epigenetic mechanisms of RIZ1 inactivation by analyzing the relationship between DNA methylation and histone modifications during regulation of RIZ1 expression. METHODS Methylation-specific PCR, RT-PCR, and immunohistochemistry were performed to examine RIZ1 methylation and expression. Dynamic changes in histone H3 lysine 9 (H3K9) modifications and histone deacetylases (HDACs) associated with the promoter were analyzed by chromatin immunoprecipitation (ChIP). RESULTS RIZ1 methylation was detected in 66.7% (32/48) HCC tissues, 6.3% (3/48) corresponding non-cancerous tissues, and 66.7% (4/6) HCC cell lines. All 32 HCC tissues with promoter methylation showed complete loss of RIZ1 protein, whereas RIZ1 protein was present in all the corresponding non-cancerous tissues. Neither 5-aza-2-deoxycitidine (5-Aza-dC) nor Trichostatin A (TSA) reversed promoter methylation, but did restore RIZ1 mRNA and resulted in the downregulation of HDAC1 but not HDAC3. However, 5-Aza-dC+TSA induced a partial reversal of promoter methylation and a markedly synergistic reactivation of RIZ1. Moreover, both HDAC1 and HDAC3 were downregulated. The ChIP assays showed 5-Aza-dC and/or TSA also contributed to the dynamic conversion of trimethylated to acetylated H3K9 at the promoter. Furthermore, a decrease in H3K9 trimethylation preceded an increase in H3K9 acetylation. CONCLUSIONS Our results suggest that promoter methylation and H3K9 modifications work together to silence the RIZ1 gene in HCC. 5-Aza-dC can restore the expression of RIZ1, as reflected by its effects on histone modification levels. This finding indicates that cooperative effects between these epigenetic modifications exist.
Collapse
Affiliation(s)
- Cuijuan Zhang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Rossi V, Staibano S, Abbondanza C, Pasquali D, De Rosa C, Mascolo M, Bellastella G, Visconti D, De Bellis A, Moncharmont B, De Rosa G, Puca GA, Bellastella A, Sinisi AA. Expression of RIZ1 protein (Retinoblastoma-interacting zinc-finger protein 1) in prostate cancer epithelial cells changes with cancer grade progression and is modulated in vitro by DHT and E2. J Cell Physiol 2009; 221:771-7. [PMID: 19746436 DOI: 10.1002/jcp.21920] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The nuclear protein methyl-transferase Retinoblastoma-interacting zinc-finger protein 1 (RIZ1) is considered to be a downstream effector of estrogen action in target tissues. Silencing of RIZ1 expression is common in many tumors. We analyzed RIZ1 expression in normal and malignant prostate tissue and evaluated whether estradiol (E2) or dihydrotestosterone (DHT) treatment modulated RIZ1 in cultured prostate epithelial cells (PEC). Moreover, we studied the possible involvement of RIZ1 in estrogen action on the EPN prostate cell line, constitutively expressing both estrogen receptor (ER)-alpha and beta. RIZ1 protein, found in the nucleus of normal PECs by immunohistochemistry, was progressively lost in cancer tissues as the Gleason score increased and was only detected in the cytoplasmic compartment. RIZ1 transcript levels, as assayed by semi-quantitative RT-PCR in primary PEC cultures, were significantly reduced in cancer cells (P < 0.05). In EPN DHT treatment significantly increased RIZ1 transcript and protein levels (P < 0.05); E2 induced a reduction of S phase without significant changes of RIZ1 expression. In E2-treated EPN cell extracts RIZ co-immunoprecipitated with ERbeta and ERalpha. Our data demonstrate that RIZ1 is expressed in normal PECs and down-regulated in cancer cells, with a switch of its sub-cellular localization from the nucleus to the cytoplasm upon cancer grade progression. RIZ1 expression levels in the PECs were modulated by DHT or E2 treatment in vitro. Furthermore, the E2 effects on ER-expressing prostate cells involve RIZ1, which confirms a possible role for ER-mediated pathways in a non-classic E(2)-target tissue.
Collapse
Affiliation(s)
- Valentina Rossi
- Dipartimento di Internistica Clinica e Sperimentale, Sezione di Endocrinologia, Seconda Università degli Studi di Napoli, Napoli, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Horvilleur E, Bauer M, Goldschneider D, Mergui X, de la Motte A, Bénard J, Douc-Rasy S, Cappellen D. p73alpha isoforms drive opposite transcriptional and post-transcriptional regulation of MYCN expression in neuroblastoma cells. Nucleic Acids Res 2008; 36:4222-32. [PMID: 18583365 PMCID: PMC2490757 DOI: 10.1093/nar/gkn394] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
MYCN activation, mainly by gene amplification, is one of the most frequent molecular events in neuroblastoma (NB) oncogenesis, and is associated with increased malignancy and decreased neuronal differentiation propensity. The frequency of concomitant loss of heterozygosity at the 1p36.3 locus, which harbours the p53 anti-oncogene homologue TP73, indicates that MYCN and p73 alterations may cooperate in the pathogenesis of NB. We have previously shown that p73 isoforms are deregulated in NB tumours and that TAp73 co-operates synergistically with p53 for apoptosis of NB cells, whereas ΔNp73 activates the expression of neuronal differentiation genes such as BTG2. Herein, using both ectopic expression and RNA interference-mediated silencing of p73 in MYCN amplified NB cells, we show that p73α isoforms inhibit MYCN expression at both transcript and protein levels, in spite of transactivator effects on MYCN promoter. To explain this paradox, we found that TAp73α exerts negative post-transcriptional effects leading to reduced MYCN mRNA stability. RNA immunoprecipitation experiments suggest that this dominant inhibitory post-transcriptional effect could be due to an interaction between the p73 protein and MYCN mRNA, a hypothesis also raised for the regulation of certain genes by the p53 protein.
Collapse
Affiliation(s)
- Emilie Horvilleur
- Interactions Molécularies et Cancer, Unité Mixte de Recherche 8126, Centre National de Recherche Scientifique-Université Paris Sud-11, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France
| | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Jiang Y, Tong D, Lou G, Zhang Y, Geng J. Expression of RUNX3 Gene, Methylation Status and Clinicopathological Significance in Breast Cancer and Breast Cancer Cell Lines. Pathobiology 2008; 75:244-51. [DOI: 10.1159/000132385] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2007] [Accepted: 01/30/2008] [Indexed: 11/19/2022] Open
|
|
16
|
Chen LB, Xu JY, Yang Z, Wang GB. Silencing SMYD3 in hepatoma demethylates RIZI promoter induces apoptosis and inhibits cell proliferation and migration. World J Gastroenterol 2007; 13:5718-24. [PMID: 17963297 PMCID: PMC4171257 DOI: 10.3748/wjg.v13.i43.5718] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of SMYD3 in hepatocellular carcinoma (HCC) development and progression and to verify whether its regulation activity was through RIZ1 inactivation.
METHODS: Expression of SMYD3 in HCC cell lines and tissues were measured; silencing of SMYD3 by RNA interference (RNAi) was effectuated, hepatoma cell proliferation, migration and apoptosis were tested, with RIZ1 CpG promoter methylation, and corresponding mRNA expression were investigated.
RESULTS: SMYD3 over-expression in HCC was associated with RIZ1 hypermethylation and mRNA down-expression. Suppression of SMYD3 expression de-methylated RIZ1 CpG promoter (P < 0.01) and increased RIZ1 mRNA expression (P < 0.01). Consequently, SMYD3 down-expression with RIZ1 de-methylation strongly inhibited hepatoma cell growth (MTT inhibitory rates: Pgenesil-1-s1 60.95% ± 7.97%, Pgenesil-1-s2 72.14% ± 9.68% vs Pgenesil-1-hk 6.89% ± 4.12%, P < 0.01) and migration (Pgenesil-1-s1 4.24% ± 1.58%, Pgenesil-1-s1 4.87% ± 0.73% vs Pgenesil-1 19.03% ± 4.63%, Pgenesil-1-hk 19.95% ± 5.21%, P < 0.01) and induced apoptosis (FCM subG1 phase Pgenesil-1-s1 19.07% ± 1.78%, Pgenesil-1-s2 17.68% ± 2.36% vs Pgenesil-1 0.47% ± 0.12%, Pgenesil-1-hk 1.46% ± 0.28%, P < 0.01. TUNEL-positive cells: Pgenesil-1-s1 40.24% ± 5.18%, Pgenesil-1-s2 38.48% ± 4.65% vs Pgenesil-1 2.18% ± 1.34%, Pgenesil-1-hk 2.84% ± 1.22%, P < 0.01) in HepG2 cells.
CONCLUSION: These results demonstrate that SMYD3 plays a critical role in the carcinogenesis and progression of HCC. The proliferation, migration induction and apoptosis inhibition activities of SMYD3 may be mediated through RIZ1 CpG promoter hypermethylation.
Collapse
|
|
17
|
Gazzerro P, Abbondanza C, D'Arcangelo A, Rossi M, Medici N, Moncharmont B, Puca GA. Modulation of RIZ gene expression is associated to estradiol control of MCF-7 breast cancer cell proliferation. Exp Cell Res 2005; 312:340-9. [PMID: 16356493 DOI: 10.1016/j.yexcr.2005.11.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2005] [Revised: 11/04/2005] [Accepted: 11/05/2005] [Indexed: 12/13/2022]
Abstract
The retinoblastoma protein-interacting zinc-finger (RIZ) gene, a member of the nuclear protein methyltransferase superfamily, is characterized by the presence of the N-terminal PR domain. The RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the PR (PRDI-BF1 and RIZ homologous) domain, RIZ2 lacks it. RIZ gene expression is altered in a variety of human cancers and RIZ1 is now considered to be a candidate tumor suppressor. Estradiol treatment of MCF-7 cells produced a selective decrease of RIZ1 transcript and an increase of total RIZ mRNA. Experiments of chromatin immunoprecipitation indicated that RIZ2 protein expression was controlled by estrogen receptor and RIZ1 had a direct repressor function on c-myc gene expression. To investigate the role of RIZ gene products as regulators of the proliferation/differentiation transition, we analyzed the effects of forced suppression of RIZ1 induced in MCF-7 cells by siRNA of the PR domain-containing form. Silencing of RIZ1 expression stimulated cell proliferation, similar to the effect of estradiol on these cells, associated with a transient increase of c-myc expression.
Collapse
Affiliation(s)
- Patrizia Gazzerro
- Dipartimento di Patologia generale, Seconda Università degli studi di Napoli, Via Luigi de Crecchio 7, I-80138 Naples, Italy
| | | | | | | | | | | | | |
Collapse
|
|
18
|
Mori T, Nomoto S, Koshikawa K, Fujii T, Sakai M, Nishikawa Y, Inoue S, Takeda S, Kaneko T, Nakao A. Decreased expression and frequent allelic inactivation of the RUNX3 gene at 1p36 in human hepatocellular carcinoma. Liver Int 2005; 25:380-8. [PMID: 15780064 DOI: 10.1111/j.1478-3231.2005.1059.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Alteration in transforming growth factor-beta signaling pathway is one of the main causes of hepatocellular carcinoma (HCC). The human runt-related transcription factor 3 gene (RUNX3) is an important component of this pathway. RUNX3 locus 1p36 is commonly deleted in a variety of human cancers, including HCC. Therefore, we examined genetic and epigenetic alterations of RUNX3 in human HCC. METHODS Five HCC cell lines and 41 patients with HCC were investigated in this study. We examined the expression of RUNX3 mRNA, methylation status of RUNX3 promoter region, loss of heterozygosity (LOH) at 1p36, and mutation analysis. These results were compared with clinicopathological data. RESULTS Promoter hypermethylation was detected in four (80%) of five HCC cell lines and 31 (75.6%) of 41 HCC tissues, confirmed by sequence of bisulfite-treated DNA. LOH was detected in 14 (37.8%) of 37 HCC. By comparison with clinicopathological data, hypermethylation was more common in hepatitis C virus antibody and formation of capsule-positive cases, and decrease of expression was correlated strongly with advanced stage and LOH-detected cases. CONCLUSION Hypermethylation and LOH appear to be common mechanisms for inactivation of RUNX3 in HCC. Therefore, RUNX3 may be an important tumor suppressor gene related to hepatocarcinogenesis.
Collapse
Affiliation(s)
- Toshiaki Mori
- Department of Surgery II, Graduate School & Faculty of Medicine, University of Nagoya, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Abstract
Several genes that contain the PR (PRDI-BF1 and RIZ) domain have been linked with human cancers. We describe here a new PR-domain-containing gene designated as PRDM5 (PFM2). A PRDM5 cDNA was isolated based on its homology to the PR domain of RIZ1 (PRDM2). The gene encodes an open reading frame of 630 amino acids and contains a PR domain in the NH-terminal region followed by 16 zinc finger motifs. Radiation hybrid analysis mapped PRDM5 to human chromosome 4q26, a region thought to harbor tumor suppressor genes for breast, ovarian, liver, lung, colon, and other cancers. The gene has a CpG island promoter and is silenced in human breast, ovarian, and liver cancers. A recombinant adenovirus expressing PRDM5 caused G2/M arrest and apoptosis upon infection of tumor cells. These results suggest that inactivation of PRDM5 may play a role in carcinogenesis.
Collapse
Affiliation(s)
- Qingdong Deng
- The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
| | | |
Collapse
|
|
20
|
MESH Headings
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Cell Adhesion/genetics
- Cell Transformation, Neoplastic
- Cell Transformation, Viral
- Chronic Disease
- Genes, cdc
- Genes, p53
- Growth Substances/physiology
- Hepacivirus/pathogenicity
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Humans
- Liver Diseases/complications
- Liver Diseases/pathology
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Neoplasm Invasiveness/genetics
- Neoplasm Metastasis
- Neovascularization, Pathologic/genetics
- Precancerous Conditions/complications
- Precancerous Conditions/pathology
Collapse
|
|
21
|
Xiao W, Park CK, Park JY, Lee JH, Kim HS, Cho YG, Kim CJ, Ahn YM, Lee JH, Song YH, Lee SH, Yoo NJ, Lee JY, Park WS. Genetic alterations of the HCCS1 gene in Korean hepatocellular carcinoma. APMIS 2003; 111:465-73. [PMID: 12780520 DOI: 10.1034/j.1600-0463.2003.1110403.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
We analyzed the gene mutations and loss of heterozygosity (LOH) of the HCCS1 gene using intragenic polymorphic markers in a series of 88 primary HCCs. We found two sequence variations at exon 5 and 14 in both normal and tumor DNAs of case 50 and 51, respectively. The variation in case 50 led to a reading frameshift and a premature stop (TGA) at codon 125 and case 51 showed amino acid change at codon 448 (Val-->Ala, GTG-->GCG). Interestingly, these variations were not found in peripheral lymphocytes of 69 normal individuals and 227 cancer patients (86 HCC, 75 unselected gastric cancer, and 66 breast cancer), suggesting that these two variations are mutation, not polymorphism. In addition, we found 14 novel intragenic polymorphic sites in the HCCS1 gene. Thirty-two (47%) of sixty-eight informative cases showed allelic loss at at least one or more intragenic polymorphic sites, but there was no significant relationship between the frequency of LOH and clinicopathologic parameters. These results suggest that mutation of the HCCS1 gene might not be a main inactivation mechanism in the development of Korean HCC and that the HCCS1 gene might be involved in acceleration of the tumorigenic process in Korean HCC.
Collapse
Affiliation(s)
- Wenhua Xiao
- Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Sasaki O, Meguro K, Tohmiya Y, Funato T, Shibahara S, Sasaki T. Altered expression of retinoblastoma protein-interacting zinc finger gene, RIZ, in human leukaemia. Br J Haematol 2002; 119:940-8. [PMID: 12472571 DOI: 10.1046/j.1365-2141.2002.03972.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The retinoblastoma protein-interacting zinc finger gene (RIZ), a member of the nuclear protein methyltransferase superfamily, is characterized by the presence of the N-terminal PR domain. The RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the PR (PRDI-BF1 and RIZ homologous) domain, RIZ2 lacks it. RIZ gene expression is altered in a variety of human cancers and RIZ1 is now considered to be a candidate tumour suppressor. To investigate the role of RIZ in leukaemogenesis, we analysed the differential expression of RIZ1 and RIZ2 by quantitative real-time reverse-transcription polymerase chain reaction assay. Our results showed that the expression of RIZ1 was significantly decreased in leukaemia cell lines (14 out of 17, 82%) and in patients with acute myeloblastic leukaemia (eight out of 14, 57%). In contrast, RIZ2 expression was increased in patients with acute lymphoblastic leukaemia (eight out of 11, 73%), compared with normal bone marrow cells. These findings indicate that suppression of RIZ1 expression or enhancement of RIZ2 expression may have an important role in leukaemogenesis.
Collapse
Affiliation(s)
- Osamu Sasaki
- Department of Rheumatology and Hematology, Tohoku University School of Medicine, Sendai, Japan
| | | | | | | | | | | |
Collapse
|
|
23
|
Sasaki O, Meguro K, Tohmiya Y, Funato T, Shibahara S, Sasaki T. Nucleotide alteration of retinoblastoma protein-interacting zinc finger gene, RIZ, in human leukemia. TOHOKU J EXP MED 2002; 196:193-201. [PMID: 12002276 DOI: 10.1620/tjem.196.193] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The retinoblastoma protein-interacting zinc finger gene (RIZ) is a zinc-finger type DNA binding protein and is postulated as a member of the nuclear protein-methyltransferase superfamily. RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the N-terminal PR (PRDI-BF1 and RIZ homologous)-domain, RIZ2 lacks it. RIZ1 is now considered as a tumor suppressor. We analyzed nucleotide alteration of RIZ gene in human leukemia. The results revealed a single nucleotide polymorphism (SNP), T1704 to A, near the conserved Rb-binding domain, leading to an amino acid change, Asp283 to Glu. Interestingly, 17 of 21 leukemia cell lines are homozygous for the T1704 allele whereas only 2 of 20 normal subjects are homozygous for the allele. In addition, one base pair deletion in the poly (A)9 tract in the coding region near the C-terminal zinc-fingers was identified, resulting in frameshift, in 1 out of 17 leukemia cell lines, but no mutation in samples from 15 patients with acute lymphoblastic leukemia (ALL) and 6 patients with adult T cell leukemia (ATL). In the PR or SH3 (src homology 3) domain of the RIZ gene, no mutation was found. These findings suggest that RIZ may be a possible target of structural alteration leading to leukemia.
Collapse
Affiliation(s)
- Osam Sasaki
- Department of Rheumatology and Hematology, Tohoku University School of Medicine, Sendai, Japan
| | | | | | | | | | | |
Collapse
|
|
24
|
Steele-Perkins G, Fang W, Yang XH, Van Gele M, Carling T, Gu J, Buyse IM, Fletcher JA, Liu J, Bronson R, Chadwick RB, de la Chapelle A, Zhang X, Speleman F, Huang S. Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily. Genes Dev 2001; 15:2250-62. [PMID: 11544182 PMCID: PMC312773 DOI: 10.1101/gad.870101] [Citation(s) in RCA: 146] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The retinoblastoma protein-interacting zinc finger gene RIZ (PRDM2) is a member, by sequence homology, of a nuclear protein-methyltransferase (MTase) superfamily involved in chromatin-mediated gene expression. The gene produces two protein products, RIZ1 that contains a conserved MTase domain and RIZ2 that lacks the domain. RIZ1 gene expression is frequently silenced in human cancers, and the gene is also a common target of frameshift mutation in microsatellite-unstable cancers. We now report studies of mice with a targeted mutation in the RIZ1 locus. The mutation inactivates RIZ1 but not RIZ2. These RIZ1 mutant mice were viable and fertile but showed a high incidence of diffuse large B-cell lymphomas (DLBL) and a broad spectrum of unusual tumors. RIZ1 deficiency also accelerated tumorigenesis in p53 heterozygous mutant mice. Finally, several missense mutations of RIZ1 were found in human tumor tissues and cell lines; one of these was particularly common in human DLBL tumors. These missense mutations, as well as the previously described frameshift mutation, all mapped to the MTase functional domains. All abolished the capacity of RIZ1 to enhance estrogen receptor activation of transcription. These data suggest a direct link between tumor formation and the MTase domain of RIZ1 and describe for the first time a tumor susceptibility gene among methyltransferases.
Collapse
|