E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone
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
2018-03-15
Source PublicationCANCER RESEARCH
ISSN0008-5472
Volume78Issue:6Pages:1418-1430
AbstractThe 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.
SubtypeArticle
DOI10.1158/0008-5472.CAN-17-2118
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Indexed BySCI
Funding OrganizationNational Natural Science Foundation of China(81472628 ; National Natural Science Foundation of China(81472628 ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; 91631107) ; 91631107) ; National Natural Science Foundation of China(81472628 ; National Natural Science Foundation of China(81472628 ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; 91631107) ; 91631107)
Language英语
WOS Research AreaOncology
WOS SubjectOncology
WOS KeywordHUMAN-PAPILLOMAVIRUS E6 ; CERVICAL-CARCINOMA CELLS ; THERAPEUTIC TARGET ; GENE-TRANSCRIPTION ; GROWTH-FACTOR ; CANCER ; ONCOPROTEINS ; APOPTOSIS ; BINDING ; GENOME
WOS IDWOS:000427620900006
Funding OrganizationNational Natural Science Foundation of China(81472628 ; National Natural Science Foundation of China(81472628 ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; 91631107) ; 91631107) ; National Natural Science Foundation of China(81472628 ; National Natural Science Foundation of China(81472628 ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Science and Technology Foundation of Shenzhen Grant(KQTD20140630100658078) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Hubei Province Health and Family Planning Scientific Research Project(WJ2017Q001) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; Natural Science Foundation of Hubei Province of China(2017CFA017) ; 91631107) ; 91631107)
Citation statistics
Document Type期刊论文
Identifierhttp://ir.ihb.ac.cn/handle/342005/50907
Collection藻类生物学及应用研究中心_水生生物分子与细胞生物学研究中心
Affiliation1.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
Recommended Citation
GB/T 7714
Chen, Xiaohua,Loo, Jun Xian,Shi, Xin,et al. E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone[J]. CANCER RESEARCH,2018,78(6):1418-1430.
APA Chen, Xiaohua.,Loo, Jun Xian.,Shi, Xin.,Xiong, Wenjun.,Guo, Yong.,...&Li, Feng.(2018).E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone.CANCER RESEARCH,78(6),1418-1430.
MLA Chen, Xiaohua,et al."E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone".CANCER RESEARCH 78.6(2018):1418-1430.
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