Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1

Haibin Liu, Junfen Xu, Yanqin Yang, Xiaohong Wang, Ethan Wu, Vladimir Majerciak, Tingting Zhang, Renske D.M. Steenbergen, Hsu Kun Wang, Nilam S. Banerjee, Yang Li, Weiguo Lu, Craig Meyers, Jun Zhu, Xing Xie, Louise T. Chow, Zhi Ming Zheng

Research output: Contribution to journalArticlepeer-review

Abstract

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3′ untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

Original languageEnglish (US)
Article numbere2014195118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number3
DOIs
StatePublished - Jan 13 2021

All Science Journal Classification (ASJC) codes

  • General

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