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UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells.

ABSTRACT: UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is an important epigenetic regulator that plays a part in DNA methylation, protein methylation and ubiquitination. It is also frequently overexpressed in many types of cancers, including cervical cancer, which is caused by human papillomavirus (HPV). In this study, we showed that UHRF1 was up-regulated in HPV oncogene E7 expressing cells and HPV-positive cervical cancer cells. We demonstrated that UHRF1 down-regulated the expression of UBE2L6 gene that encodes the ISG15-conjugating enzyme UbcH8. Overexpression of UHRF1 reduced UBE2L6 while knockdown UHRF1 elevated the expression of UBE2L6. We showed that UHRF1 regulated UBE2L6 gene by promoter hypermethylation in cervical cancer cells. Consistent with the functions of UHRF1, restored expression of UbcH8 induced apoptosis. These findings establish UBE2L6 as a novel target of UHRF1 that regulates the apoptosis function of UHRF1. Our studies suggest that UHRF1/ UbcH8 can be manipulated for therapy in cervical cancer.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC5914733 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells.

Zhang Qishu Q Qiao Lijun L Wang Xiao X Ding Changkuan C Chen Jason J JJ

Cell cycle (Georgetown, Tex.) 20180131 3

UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is an important epigenetic regulator that plays a part in DNA methylation, protein methylation and ubiquitination. It is also frequently overexpressed in many types of cancers, including cervical cancer, which is caused by human papillomavirus (HPV). In this study, we showed that UHRF1 was up-regulated in HPV oncogene E7 expressing cells and HPV-positive cervical cancer cells. We demonstrated that UHRF1 down-regulated the expressio ...[more]

PMID: 29157076

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Project description:DNA methylation, and consequent down-regulation, of tumour suppressor genes occurs in response to epigenetic stimuli during cancer development. Similarly, human oncoviruses, including human papillomavirus (HPV), up-regulate and augment DNA methyltransferase (DNMT) and histone deacetylase (HDAC) activities, thereby decreasing tumour suppressor genes (TSGs) expression. Ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), an epigenetic regulator of DNA methylation, is overexpressed in HPV-induced cervical cancers. Here, we investigated the role of UHRF1 in cervical cancer by knocking down its expression in HeLa cells using lentiviral-encoded short hairpin (sh)RNA and performing cDNA microarrays. We detected significantly elevated expression of thioredoxin-interacting protein (TXNIP), a known TSG, in UHRF1-knockdown cells, and this gene is hypermethylated in cervical cancer tissue and cell lines, as indicated by whole-genome methylation analysis. Up-regulation of UHRF1 and decreased TXNIP were further detected in cervical cancer by western blot and immunohistochemistry and confirmed by Oncomine database analysis. Using chromatin immunoprecipitation, we identified the inverted CCAAT domain-containing UHRF1-binding site in the TXNIP promoter and demonstrated UHRF1 knockdown decreases UHRF1 promoter binding and enhances TXNIP expression through demethylation of this region. TXNIP promoter CpG methylation was further confirmed in cervical cancer tissue by pyrosequencing and methylation-specific polymerase chain reaction. Critically, down-regulation of UHRF1 by siRNA or UHRF1 antagonist (thymoquinone) induces cell cycle arrest and apoptosis, and ubiquitin-specific protease 7 (USP7), which stabilises and promotes UHRF1 function, is increased by HPV viral protein E6/E7 overexpression. These results indicate HPV might induce carcinogenesis through UHRF1-mediated TXNIP promoter methylation, thus suggesting a possible link between CpG methylation and cervical cancer.

Dataset Information

UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells.

Publications

UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells.

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