Piwil2 is reactivated by HPV oncoproteins and initiates cell reprogramming via epigenetic regulation during cervical cancer tumorigenesis.
The human papillomavirus (HPV) oncoproteins E6 and E7 are risk factors that are primarily responsible for the initiation and progression of cervical cancer, and they play a key role in immortalization and transformation by reprogramming differentiating host epithelial cells. It is unclear how cervical epithelial cells transform into tumor-initiating cells (TICs). Here, we observed that the germ stem cell protein Piwil2 is expressed in pre-cancerous and malignant lesions of the cervix and cervical cancer cell lines with the exception of the non-HPV-infected C33a cell line. Knockdown of Piwil2 by shRNA led to a marked reduction in proliferation and colony formation, in vivo tumorigenicity, chemo-resistance, and the proportion of cancer stem-like cells. In contrast, Piwil2 overexpression induced malignant transformation of HaCaT cells and the acquisition of tumor-initiating capabilities. Gene-set enrichment analysis revealed embryonic stem cell (ESC) identity, malignant biological behavior, and specifically, activation targets of the cell reprogramming factors c-Myc, Klf4, Nanog, Oct4, and Sox2 in Piwil2-overexpressing HaCaT cells. We further confirmed that E6 and E7 reactivated Piwil2 and that E6 and E7 overexpression resulted in a similar gene-set enrichment pattern as Piwil2 overexpression in HaCaT cells. Moreover, Piwil2 overexpression or E6 and E7 activation induced H3K9 acetylation but reduced H3K9 trimethylation, which contributed to the epigenetic reprogramming and ESC signature maintenance, as predicted previously. Our study demonstrates that Piwil2, reactivated by the HPV oncoproteins E6 and E7, plays an essential role in the transformation of cervical epithelial cells to TICs via epigenetics-based cell reprogramming.
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.
Dingqing
D
Feng
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.
Keqin
K
Yan
Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.
Ying
Y
Zhou
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.
Haiyan
H
Liang
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.
Jing
J
Liang
Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.|Department of Gynecology and Oncology, Anhui Provincial Cancer Hospital, Hefei, China.
Weidong
W
Zhao
School of Medicine, Tsinghua University, Beijing, China.
Zhongjun
Z
Dong
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.
Bin
B
Ling
D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D063185:Epigenetic Repression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000502:physiology* / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D023041:Xenograft Model Antitumor Assays
D060565:Argonaute Proteins; C068651:E6 protein, Human papillomavirus type 16; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D009856:Oncogene Proteins, Viral; C486868:PIWIL2 protein, human; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16
HPV oncoprotein; Piwil2; cell reprogramming; cervical cancer; tumor initiating cell