Abstract
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.
Highlights
The PIWI family of proteins has emerged as new players in the transcriptional and posttranscriptional regulation of gene expression [1,2,3,4,5]
In HeLa, SiHa, and CaSki cervical cancer cell lines, which contain an integrated HR-human papillomavirus (HPV) genome of type 18, 16, or both, respectively, Piwil2 expression was observed; in the C33a cell line, which is negative for High-risk human papillomavirus (HR-HPV) DNA and RNA, no expression was detectable (Figure 1d)
These results suggest that reactivation of Piwil2 in cervical cancer may be related to the integration of HR-HPV DNA into the host cell genome
Summary
The PIWI family of proteins has emerged as new players in the transcriptional and posttranscriptional regulation of gene expression [1,2,3,4,5]. The members of the PIWI subfamily are characterized by highly conserved PIWI and PAZ domains [3] and play crucial roles for gametogenesis, stem cell self-renewal, and epigenetic regulation in various organisms [6, 7]. Four members of the PIWI subfamily (Piwil , and 4) have been identified in the human genome. The underlying mechanism of Piwil in tumorigenesis may differ among various cancer cells, such as anti-apoptosis by activation of the Stat3/Bcl-XL pathway [9], suppressing P53 expression by enhancing www.impactjournals.com/oncotarget. Piwil is predominantly expressed in cancer stem cells (CSCs) and in precancerous stem cells (pCSCs) [10, 11, 17,18,19], indicating that it might play an important role in tumor initiation
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