The Tumor Suppressor Hic1 Maintains Chromosomal Stability Independent of Tp53
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PROVIDER: PRJNA412520 | ENA |
REPOSITORIES: ENA
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Project description:Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of-heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex. Using a conditional knockout mouse model of tumor initiation, we now show that inactivation of Hic1 results in cell cycle arrest, premature senescence, chromosomal instability and spontaneous transformation in vitro. This phenocopies the effects of deleting Brca1, a component of the homologous recombination DNA repair pathway, in mouse embryonic fibroblasts. These effects did not appear to be mediated by deregulation of Hic1 target gene expression or loss of Tp53 function, and rather support a role for Hic1 in maintaining genome integrity during sustained replicative stress. Loss of Hic1 function also cooperated with activation of oncogenic KRas in the adult airway epithelium of mice, resulting in the formation of highly pleomorphic adenocarcinomas with a micropapillary phenotype in vivo. These results suggest that loss of Hic1 expression in the early stages of tumor formation may contribute to malignant transformation through the acquisition of chromosomal instability.
| S-EPMC5886987 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-10-31 | GSE104394 | GEO
Project description:Background: TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers. Methods: Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through In vitro and in vivo experiments, we explored proliferation, transformation potential, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis. Results: Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability. Conclusions: PRJNA1092607Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.
2024-06-23 | PXD051459 | Pride
Project description:Hypermethylated in cancer 1 (HIC1) represents a prototypic tumor suppressor gene frequently inactivated by DNA methylation in many types of solid tumors. The gene encodes a sequence-specific transcriptional repressor controlling expression of several genes involved in the cycle or stress control. In this study, we employed a conditional Hic1 allele to identify genes influenced by the loss of Hic1.
2016-02-01 | E-MTAB-3486 | biostudies-arrayexpress
Project description:Atr maintains chromosomal integrity during postnatal cerebellar neurogenesis
| PRJNA338316 | ENA
Project description:The tumor suppressor gene HIC1 (Hypermethylated in Cancer 1) is essential for mammalian development and is epigenetically silenced in many human tumors. Functionally, HIC1 is involved in a complex pathway regulating P53 tumor-suppression activity. HIC1 encodes a sequence-specific transcriptional repressor containing five Krüppel-like C2H2 zinc fingers but only a few genes regulated by HIC1 have been reported, including SIRT1. Keywords: Time Series Design
2007-12-13 | GSE9854 | GEO
Project description:TP53 loss initiates chromosomal instability in fallopian tube epithelial cells
| PRJNA756361 | ENA
Project description:This study aimed to further our understanding of the role that hypermethylatioted in cancer 1 (HIC1) plays in prostate cancer (PCa) development. Microarrays were searched for some genes that had correlated expression with HIC1 mRNA. Our data showed that HIC1 promoter hypermethylation was presented in cell lines, tissues and plasma of PCa patients. According to fold-change screening between restoring expression of HIC1 and its respective control cells, both up-regulated and down-regulated genes were commonly observed in PC3 and C4-2B cells. The restoring expression HIC1 in PCa lines were respectively noted as PC3-HIC1 and C4-2B-HIC1 cells, and the respective controls were noted as C4-2B-GFP and PC3-GFP cells.
2012-11-17 | E-GEOD-42336 | biostudies-arrayexpress
Project description:This study aimed to further our understanding of the role that hypermethylatioted in cancer 1 (HIC1) plays in breast cancer progression. Microarrays were searched for some genes that had correlated expression with HIC1 mRNA. According to fold-change screening between restoring expression of HIC1 and its respective control cells in MDA-MB-231 cells, or HIC1 knockdown and its respective control cells in HBL100, both up-regulated and down-regulated genes were shown. The restoring expression HIC1 in MDA-MB-231 cells were respectively noted as MDAMB-231-HIC1 and the respective controls were noted as MDA-MB-231-GFP cells. HIC1 knockdown in HBL100 cells were noted as HBL100-shHIC1 and the respective control HBL100-shCtrl cell.
2013-08-22 | E-GEOD-50061 | biostudies-arrayexpress
Project description:To identify the target of miR-212, miR-132 and HIC1, we have employed whole genome microarray expression profiling on the human breast cancer MCF7 cells. To generate miR-212/132 or HIC1 inducible MCF7 cells, doxycycline-dependent miR-212/132 or HIC1 gene expression system was used. Either Tet-ON miR-212/132 MCF7 or Tet-ON HIC1 MCF7 were treated with 1μg/ml of Doxycycline for 36 hours with EMEM containing 0.01 mg/ml bovine insulin and 10% FCS. Two independent experiments were performed.
2014-07-29 | E-GEOD-37945 | biostudies-arrayexpress