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题名: E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone
作者: Chen, Xiaohua1, 2; Loo, Jun Xian1; Shi, Xin1; Xiong, Wenjun1, 3; Guo, Yong4; Ke, Haiqiang1; Yang, Mingkun5; Jiang, Yanping6; Xia, Siyu1; Zhao, Min1; Zhong, Shan1; He, Chunjiang1; Fu, Li7, 8; Li, Feng1
刊名: CANCER RESEARCH
发表日期: 2018-03-15
DOI: 10.1158/0008-5472.CAN-17-2118
卷: 78, 期:6, 页:1418-1430
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ; Life Sciences & Biomedicine
类目[WOS]: Oncology
研究领域[WOS]: Oncology
英文摘要: The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET.
关键词[WOS]: HUMAN-PAPILLOMAVIRUS E6 ; CERVICAL-CARCINOMA CELLS ; THERAPEUTIC TARGET ; GENE-TRANSCRIPTION ; GROWTH-FACTOR ; CANCER ; ONCOPROTEINS ; APOPTOSIS ; BINDING ; GENOME
语种: 英语
项目资助者: National Natural Science Foundation of China(81472628 ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; 91631107)
WOS记录号: WOS:000427620900006
ISSN号: 0008-5472
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/342005/50907
Appears in Collections:水生生物分子与细胞生物学研究中心_期刊论文

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作者单位: 1.Wuhan Univ, Sch Basic Med Sci, Dept Med Genet, Wuhan, Hubei, Peoples R China
2.Hubei Prov Key Lab Dev Originated Dis, Wuhan, Hubei, Peoples R China
3.Hubei Prov Key Lab Allergy & Immunol, Wuhan, Hubei, Peoples R China
4.161 Hosp PLA, Dept Pathol, Wuhan, Hubei, Peoples R China
5.Chinese Acad Sci, Inst Hydrobiol, Key Lab Algal Biol, Wuhan, Hubei, Peoples R China
6.Wuhan Univ, Renmin Hosp, Dept Obstet & Gynecol, Wuhan, Hubei, Peoples R China
7.Shenzhen Univ, Sch Med, Dept Pharmacol, Shenzhen, Peoples R China
8.Shenzhen Univ, Sch Med, Canc Res Ctr, Shenzhen, Peoples R China
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