Dataset Information

HPV-mediated nuclear export of HP1? drives cervical tumorigenesis by downregulation of p53.

ABSTRACT: E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1? (HP1?) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1? is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1? through the interaction between the NES sequence of HP1? and exportin-1. The mutation of the NES sequence in HP1? led to nuclear retention of HP1? and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1? directly suppresses the expression of UBE2L3 which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of UBE2L3 by overexpression of HP1? suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1?.

SUBMITTER: Yi SA

PROVIDER: S-EPMC7429875 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53.

Yi Sang Ah SA Lee Dong Hoon DH Kim Go Woon GW Ryu Hyun-Wook HW Park Jong Woo JW Lee Jaecheol J Han Jihoon J Park Jee Hun JH Oh Hwamok H Lee Jieun J Choi Junjeong J Kim Hyun-Soo HS Kang Hyeok Gu HG Kim Da-Hyun DH Chun Kyung-Hee KH You Jueng Soo JS Han Jeung-Whan JW Kwon So Hee SH

Cell death and differentiation 20200323 9

E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heteroch ...[more]

PMID: 32203172

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Project description:BackgroundRho guanine nucleotide exchange factor 10-like protein (ARHGEF10L) is a member of the guanine nucleotide exchange factor family, which regulates Rho GTPase activities, thus contributing to tumorigenesis. Our previous study demonstrated a strong association between the ARHGEF10L gene and the risk of cervical carcinoma. This study investigated the pathogenic role and mechanism of ARHGEF10L in cervical tumors.MethodsThe HeLa cell line, which was derived from cervical carcinoma, was transfected with ARHGEF10L-overexpressing plasmids or anti-ARHGEF10L siRNA. Cell counting kit-8 assays, wound-healing assays, and cell apoptosis assays were performed to investigate the effects of ARHGEF10L on cell activities. A Rho pull-down assay and RNA-sequencing analysis were performed to investigate the pathogenic pathway of ARHGEF10L involvement in cervical tumors.ResultsARHGEF10L overexpression promoted cell proliferation and migration, reduced cell apoptosis, and induced epithelial-to-mesenchymal transition (EMT) via downregulation of E-cadherin and upregulation of N-cadherin and Slug in transfected HeLa cells. The overexpression of ARHGEF10L also upregulated GTP-RhoA, ROCK1, and phospho-ezrin/radixin/moesin (ERM) expression in HeLa cells. RNA-sequencing analysis detected altered transcription of 31 genes in HeLa cells with ARHGEF10L overexpression. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) pathway analyses identified significant differences in cyclin-dependent protein serine/threonine kinase activity, cell responses to vitamin A, and Toll-like receptor signaling pathways. Both real-time PCR and Western blotting verified the increased expression of heat shock 70 kDa protein 6 (HSPA6) in ARHGEF10L-overexpressing HeLa cells. Since we reported that ARHGEF10L played a role through RhoA-ROCK1-ERM signaling, an important pathway in tumorigenesis, and stimulated EMT and HSPA6 expression in liver tumors and gastric tumor cells, we suggest that ARHGEF10L is a novel oncogene in many tumors.

Dataset Information

HPV-mediated nuclear export of HP1? drives cervical tumorigenesis by downregulation of p53.

Publications

HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53.

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