• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/metabolism
• Male
• Female
• Immunohistochemistry
• Middle Aged
• Adenoma/pathology
• Adenoma/metabolism
• Biomarkers, Tumor/metabolism
• Aged
• Adult
• Tumor Suppressor Proteins/metabolism
• Transcription Factors/metabolism
• Membrane Proteins

• biochemistry
• cancer therapeutic resistance

• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• Humans
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Acetylation/drug effects
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Carcinoma, Squamous Cell/drug therapy
• Cell Line, Tumor
• Transcription Factors/metabolism
• Transcription Factors/genetics
• Lysine Acetyltransferase 5/metabolism
• Lysine Acetyltransferase 5/genetics
• Tumor Suppressor Proteins/metabolism
• Tumor Suppressor Proteins/genetics
• Antineoplastic Agents/pharmacology
• Skin Neoplasms/metabolism
• Skin Neoplasms/genetics
• Skin Neoplasms/pathology
• Skin Neoplasms/drug therapy
• Apoptosis/drug effects
• Histone Acetyltransferases/metabolism
• Histone Acetyltransferases/genetics
• Gene Expression Regulation, Neoplastic/drug effects

• R01 CA280075 NCI NIH HHS
• 1R01CA280075 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.

• Hepatocellular carcinoma
• p53
• Tumour suppressor gene
• Murine double minute 2
• Chemoresistance

• cancer
• p63
• signaling
• therapeutic strategy

• Humans
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/therapy
• Transcription Factors/metabolism
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor

• R21 OD018332 NIH HHS
• F32 CA225134 NCI NIH HHS
• F31 CA247400 NCI NIH HHS
• P30 CA045508 NCI NIH HHS
• R01 CA190997 NCI NIH HHS

• DNA damage
• cancer progression
• p53
• p63
• protein-protein interactions (PPI)
• stem cell

• DNA binding landscape
• chromosomes
• gene expression
• gene regulatory network
• genetics
• genomics
• human
• p53
• p63
• resource
• squamous cell carcinoma

• Binding Sites
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Computational Biology
• DNA/genetics
• DNA/metabolism
• Databases, Genetic
• Gene Expression Regulation
• Gene Regulatory Networks
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/mortality
• Humans
• Prognosis
• Protein Binding
• Squamous Cell Carcinoma of Head and Neck/genetics
• Squamous Cell Carcinoma of Head and Neck/metabolism
• Squamous Cell Carcinoma of Head and Neck/mortality
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism

• FI 1993/2-1 Deutsche Forschungsgemeinschaft
• 031L016D Bundesministerium für Bildung und Forschung
• Open Access Fund Leibniz Association

Transmembrane and ubiquitin-like domain-containing 1 (Tmub1) inhibits hepatocyte proliferation during liver regeneration, but its role in hepatocellular carcinoma (HCC) has yet to be revealed. In this study, we show that the levels of Tmub1 were significantly lower in HCC tissues and cells than they were in adjacent tissues and normal hepatic cells, and the low levels of Tmub1 indicated a poor prognosis in HCC patients. Xenograft growth assay revealed that Tmub1 represses HCC growth in vivo. In addition, Tmub1 formed a protein complex with apoptosis-associated protein tumor protein 63 (p63), especially with the ΔN isoforms (ΔNp63α, β, and γ). Further loss- and gain-of-function analyses indicated that Tmub1 promotes apoptosis of Hep3B and MHCC-LM3 cells. Tmub1 decreased the protein expression of ΔNp63, and the pro-apoptotic effect of Tmub1 can be reversed by ΔNp63 isoforms (α, β, and γ). Additionally, we report that Tmub1 promotes the ubiquitination and degradation of ΔNp63 proteins. Finally, we confirmed in HCC tissues that Tmub1 is negatively correlated with ΔNp63 and positively correlated with the level of apoptosis. Taken together, Tmub1 suppresses HCC by enhancing the ubiquitination and degradation of ΔNp63 isoforms to induce HCC cell apoptosis. These findings provide a potential strategy for the management of HCC.

• cell apoptosis
• hepatocellular carcinoma
• post-translational modification
• transmembrane and ubiquitin-like domain containing 1 protein
• tumor protein 63
• tumor suppressor
• ubiquitination

• CRISPR screen
• head and neck carcinoma
• lung cancer
• p53
• p63

• DNA damage response
• chromatin
• chromatin modification
• chromatin regulation
• epigenetics
• p53
• p63
• transcription
• transcription factor
• transcription regulation

• Cholangiocarcinoma
• Hepatoblastoma
• Hepatocellular carcinoma
• Multidrug resistance
• Targeted therapies

• ectoderm
• endoderm
• mammal
• organism
• organogenesis

• Adult Stem Cells/physiology
• Animals
• Cell Differentiation/physiology
• Humans
• Neoplasms/metabolism
• Neoplasms/therapy
• Regeneration/physiology
• Salivary Glands/cytology
• Salivary Glands/metabolism

• MR/K017047/1 Medical Research Council
• MR/S005544/1 Medical Research Council
• R01 DE024188 NIDCR NIH HHS
• R35 DE028255 NIDCR NIH HHS

Avoidance of apoptosis induced by anticancer drugs is an essential factor of carcinogenesis and a hallmark of resistance to cancer therapy. Human telomerase reverse transcriptase receptor (hTERTR) is a potential anti-cancer agent for inhibiting tumor growth. Family with sequence similarity 96 member A (FAM96A) is a ubiquitous, conserved protein and possesses apoptosome-activating and pro-apoptotic tumor suppressor potential in hepatocellular carcinoma (HCC). In the present study, hTERTR and FAM96A were identified as efficient anti-cancer agents for activating apoptosomes and reducing tumor growth. The potential tumor suppressor function of combination treatment with hTERTR and FAM96A in HCC was also investigated. hTERTR and FAM96A proteins were expressed by genetic engineering and their anti-cancer function was explored in vitro and in vivo. Effects of hTERTR and FAM96A on improvement of apoptotic sensitivity and inhibition of migration and invasion were examined in cancer cells and in a mouse model. The present results demonstrated that the therapeutic effects of hTERTR and FAM96A were effective for inhibiting tumor growth and inducing apoptosis of HCC cells in H22-bearing nude mice compared with single agent treatment. hTERTR and FAM96A were found to bind with apoptotic protease activating factor 1 and human telomerase reverse transcriptase, which enhanced the apoptosis of tumor cells and apoptosis sensitivity. In addition, hTERTR and FAM96A therapy enhanced cytotoxic effects by cytotoxic T lymphocyte responses, interferon-γ release, T lymphocytes infiltration and apoptosis on tumor cells. Furthermore, hTERTR and FAM96A protein inhibited tumor growth in HCC mice. In conclusion, the present findings suggested that combination therapy with hTERTR and FAM96A may serve as novel tumor suppressor agents.

• apoptosis
• hepatocellular carcinoma
• human telomerase reverse transcriptase receptor-family with sequence similarity 96 member A
• tumor therapy

p53 is a transcription factor that suppresses tumor growth through regulation of dozens of target genes with diverse biological functions. The activity of this master transcription factor is inactivated in nearly all tumors, either by mutations in the TP53 locus or by oncogenic events that decrease the activity of the wild-type protein, such as overexpression of the p53 repressor MDM2. However, despite decades of intensive research, our collective understanding of the p53 signaling cascade remains incomplete. In this review, we focus on recent advances in our understanding of mechanisms of p53-dependent transcriptional control as they relate to five key areas: (1) the functionally distinct N-terminal transactivation domains, (2) the diverse regulatory roles of its C-terminal domain, (3) evidence that p53 is solely a direct transcriptional activator, not a direct repressor, (4) the ability of p53 to recognize many of its enhancers across diverse chromatin environments, and (5) mechanisms that modify the p53-dependent transcriptional program in a context-dependent manner.

Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines.

HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIP_S/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells.

The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIP_L/cFLIP_S ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIP_L upregulation.

The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/virology
• Cell Death
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Hepatitis B/complications
• Hepatitis B virus/isolation & purification
• Humans
• Liver/metabolism
• Liver/pathology
• Liver/virology
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Liver Neoplasms/virology
• Liver Transplantation/methods
• Male
• Protein Isoforms/genetics
• Receptors, Death Domain/genetics
• Transcription Factors/genetics
• Tumor Protein p73/genetics
• Tumor Suppressor Proteins/genetics

• Instituto de Salud Carlos III
• Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía
• Consejería de Salud (Junta de Andalucia, ES)
• CIBER

Paclitaxel (PTX) is frequently used in the clinical treatment of solid tumors. But the PTX-resistance is a great obstacle in cancer treatment. Exploration of the mechanisms of drug resistance suggests that tumor suppressor genes (TSGs) play a key role in the response of chemotherapeutic drugs. TSGs, a set of genes that are often inactivated in cancers, can regulate various biological processes. In this study, an overview of the contribution of TSGs to PTX resistance and their underlying relationship in cancers are reported by using GeneMANIA, a web-based tool for gene/protein function prediction.

Using PubMed online database and Google web site, the terms “paclitaxel resistance” or “taxol resistance” or “drug resistance” or “chemotherapy resistance”, and “cancer” or “carcinoma”, and “tumor suppressor genes” or “TSGs” or “negative regulated protein” or “antioncogenes” were searched and analyzed. GeneMANIA data base was used to predict gene/protein interactions and functions.

We identified 22 TSGs involved in PTX resistance, including BRCA1, TP53, PTEN, APC, CDKN1A, CDKN2A, HIN-1, RASSF1, YAP, ING4, PLK2, FBW7, BLU, LZTS1, REST, FADD, PDCD4, TGFBI, ING1, Bax, PinX1 and hEx. The TSGs were found to have direct and indirect relationships with each other, and thus they could contribute to PTX resistance as a group. The varied expression status and regulation function of the TSGs on cell cycle in different cancers might play an important role in PTX resistance.

A further understanding of the roles of tumor suppressor genes in drug resistance is an important step to overcome chemotherapy tolerance. Tumor suppressor gene therapy targets the altered genes and signaling pathways and can be a new strategy to reverse chemotherapy resistance.

• GeneMANIA
• Molecular functions
• Paclitaxel resistance
• Tumor suppressor genes

p53 is an important tumor suppressor gene, which is stimulated by cellular stress like ionizing radiation, hypoxia, carcinogens, and oxidative stress. Upon activation, p53 leads to cell-cycle arrest and promotes DNA repair or induces apoptosis via several pathways. p63 and p73 are structural homologs of p53 that can act similarly to the protein and also hold functions distinct from p53. Today more than 40 different isoforms of the p53 family members are known. They result from transcription via different promoters and alternative splicing. Some isoforms have carcinogenic properties and mediate resistance to chemotherapy. Therefore, expression patterns of the p53 family genes can offer prognostic information in several malignant tumors. Furthermore, the p53 family constitutes a potential target for cancer therapy. Small molecules (e.g., Nutlins, RITA, PRIMA-1, and MIRA-1 among others) have been objects of intense research interest in recent years. They restore pro-apoptotic wild-type p53 function and were shown to break chemotherapeutic resistance. Due to p53 family interactions small molecules also influence p63 and p73 activity. Thus, the members of the p53 family are key players in the cellular stress response in cancer and are expected to grow in importance as therapeutic targets.

• apoptosis
• cancer
• cellular stress
• chemosensitivity
• p53
• p63
• p73

Thyroid iodide accumulation via the sodium/iodide symporter (NIS; SLC5A5) has been the basis for the longtime use of radio-iodide in the diagnosis and treatment of thyroid cancers. NIS is also expressed, but poorly functional, in some non-thyroid human cancers. In particular, it is much more strongly expressed in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) cell lines than in primary human hepatocytes (PHH). The transcription factors and signaling pathways that control NIS overexpression in these cancers is largely unknown. We identified two putative regulatory clusters of p53-responsive elements (p53REs) in the NIS core promoter, and investigated the regulation of NIS transcription by p53-family members in liver cancer cells. NIS promoter activity and endogenous NIS mRNA expression are stimulated by exogenously expressed p53-family members and significantly reduced by member-specific siRNAs. Chromatin immunoprecipitation analysis shows that the p53–REs clusters in the NIS promoter are differentially occupied by the p53-family members to regulate basal and DNA damage-induced NIS transcription. Doxorubicin strongly induces p53 and p73 binding to the NIS promoter, leading to an increased expression of endogenous NIS mRNA and protein in HCC and CCA cells, but not in PHH. Silencing NIS expression reduced doxorubicin-induced apoptosis in HCC cells, pointing to a possible role of a p53-family-dependent expression of NIS in apoptotic cell death. Altogether, these results indicate that the NIS gene is a direct target of the p53 family and suggests that the modulation of NIS by DNA-damaging agents is potentially exploitable to boost NIS upregulation in vivo.

The dysfunction of cell apoptosis signaling is involved in carcinogenesis. P53 up-regulated modulator of apoptosis (PUMA), a pro-apoptosis gene that has been found for a decade, encodes a protein that is one of Bcl-2 members and can induce apoptosis via the mitochondrial pathway. It is considered that mutation of the PUMA gene is not involved in carcinogenesis, because mutation of the PUMA gene has not been found in many types of tumors until now. The expression of PUMA protein is regulated transcriptionally via ER stress, p53, JNK, FOXO3a and E2F1 signaling or post-translationally by phosphorylation. Several studies have showed that the down-regulation of PUMA protein in cancer tissue is associated with carcinogenesis, lymph node metastasis and tumor prognosis, and that up-regulation of PUMA induces the inhibition of cancer cell proliferation. Increasing new findings on the precise role of PUMA in the regulation of cancer development provide new insights into the potential use of PUMA as a target for the prevention and treatment of cancer.

• Cancer
• P53 up-regulated modulator of apoptosis
• Apoptosis

p63 is up-regulated in melanoma and prevents nuclear accumulation of p53.

The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents.

ΔNp63α is a potent oncogene in squamous cell carcinomas (SCCs) and a pro-proliferative factor expressed by basal epithelial cells. ΔNp63α functions both as a transcriptional repressor and activator, but it is not clear how these activities contribute to its oncogenic potential. ΔNp63α was proposed to function as a dominant negative of the related factor p53. Additionally, ΔNp63α was shown to inactivate its family member TAp73 and mediate recruitment of repressive histone deacetylase (HDAC) complexes to chromatin. Recently, we identified a new mechanism of repression involving recruitment of histone H2A/H2A.Z exchange complexes and H2A.Z deposition at ΔNp63α target genes. Here, we aimed to define the possible co-occurrence of the various repressive mechanisms. In lung SCC cells expressing ΔNp63α, p53 and TAp73, we found that ΔNp63α exerts its pro-proliferative and transcriptional repressive effects in a manner independent of p53, TAp73 and histone H3 and H4 deacetylation. Instead, ΔNp63α target genes are differentiated from non-target genes within the p53 network by incorporation and accumulation of acetylated H2A.Z. These results indicate that ΔNp63α utilizes multiple mechanisms of repression in diverse epithelial and SCC cells.

• H2A.Z
• histone acetylation
• oncogene
• p53
• p73
• squamous cell carcinoma
• transcriptional repression

Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications.

• Base Sequence
• Chromosomes, Human, Pair 3/genetics
• Cohort Studies
• DNA Mutational Analysis
• Gene Frequency
• Genetic Association Studies
• Humans
• In Situ Hybridization, Fluorescence
• Incidence
• Lymphoma, B-Cell/epidemiology
• Lymphoma, B-Cell/genetics
• Lymphoma, B-Cell/metabolism
• Lymphoma, B-Cell/pathology
• Lymphoma, Non-Hodgkin/epidemiology
• Lymphoma, Non-Hodgkin/genetics
• Lymphoma, Non-Hodgkin/metabolism
• Lymphoma, Non-Hodgkin/pathology
• Molecular Sequence Data
• Nuclear Proteins/genetics
• Oncogene Proteins, Fusion/genetics
• Receptors, Cytoplasmic and Nuclear/genetics
• Repressor Proteins/genetics
• Transcription Factors/genetics
• Tumor Suppressor Proteins/genetics

• U01 CA114778 NCI NIH HHS
• 1U01CA114778 NCI NIH HHS
• CIHR
• HHSN261200800001C NCI NIH HHS
• P50 CA130805 NCI NIH HHS
• P50CA130805-01 NCI NIH HHS
• HHSN261200800001E NCI NIH HHS

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Apoptosis
• Apoptosis Regulatory Proteins/metabolism
• Autophagy
• Humans
• Imidazoles/pharmacology
• Neoplasms/drug therapy
• Neoplasms/pathology
• Piperazines/pharmacology
• Protein Stability
• Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors
• Tumor Suppressor Protein p53/chemistry
• Tumor Suppressor Protein p53/metabolism

• GGP09133 Telethon
• MC_U132670600 Medical Research Council