Journal Article

HPV16 E6 and E7 upregulate the histone lysine demethylase KDM2B through the c-MYC/miR-146a-5p axys

Peta, Elektra, Di Camillo, Barbara, Masi, Giulia, Manfrin, Erminia, Sinigaglia, Alessandro, Messa, Lorenzo, Loregian, Arianna, Martignoni, Guido, Trevisan, Marta, Brunelli, Matteo, Palù, Giorgio, Barzon, Luisa, Grassi, Angela

2018

Overview

Persistent infection by high-risk human papillomaviruses (HPVs) is associated with the development of cervical cancer and a subset of anogenital and head and neck squamous cell carcinomas. Abnormal expression of cellular microRNAs (miRNAs) plays an important role in the development of cancer, including HPV-related tumors. In this study, we demonstrated that miR-146a-5p was down-regulated by E6 and, less efficiently, by E7 of high-risk HPV16 in keratinocytes and the presence of low levels of this miRNA in cervical carcinoma cell lines and in high-risk HPV-positive cervical specimens. Down-regulation of miR-146a-5p was mediated at least in part by the transcription repressor c-MYC, through binding sites in the miR-146a promoter. Overexpression of miR-146a-5p significantly inhibited proliferation and migration of keratinocytes and cervical cancer cells. The histone demethylase KDM2B was validated as a new direct target of miR-146a-5p and two putative binding sites for miR-146a-5p were identified in its 3′UTR sequence. Western blot analysis and immunohistochemistry showed that KDM2B was overexpressed in HPV16 E6/E7-positive keratinocytes, in cervical cancer cell lines, and in a subset of invasive cervical carcinomas and HPV-positive laryngeal squamous cell carcinomas. In these tumors, KDM2B overexpression was associated with c-MYC copy number gain. In vitro, silencing of KDM2B inhibited proliferation of cervical cancer cells. In conclusion, this study identified a novel player, the hystone demethylase KDM2B, in HPV-mediated tumorigenesis. E6 and, less efficiently, E7 of high-risk HPV16 up-regulated KDM2B expression in human keratinocytes through a pathway involving overexpression of c-MYC, which in turn downregulated miR-146a-5p.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 3' Untranslated regions / 38/32 / 42/89 / 45/44 / 45/61 / 45/70 / 631/326/596 / 631/67/1858 / 82/51 / 82/80 / Anogenital / Apoptosis / Binding sites / c-Myc protein / Cancer / Cancer cells / Cancer research / Carcinoma / Care and treatment / Cell Biology / Cell proliferation / Cell Transformation, Viral - genetics / Cells, Cultured / Cellular signal transduction / Cervical cancer / Cervical carcinoma / Copy number / Development and progression / F-Box Proteins - genetics / Female / Gene Expression Regulation, Enzymologic / Genetic aspects / Genetic regulation / Head & neck cancer / Head and neck carcinoma / Health aspects / HEK293 Cells / HeLa Cells / Human Genetics / Human papillomavirus / Humans / Immunohistochemistry / Infection / Internal Medicine / Invasiveness / Jumonji Domain-Containing Histone Demethylases - genetics / Keratinocytes / Laryngeal cancer / Laryngeal carcinoma / Lysine / Medicine / Medicine & Public Health / MicroRNA / MicroRNAs - physiology / miRNA / Myc protein / Oncogene Proteins, Viral - physiology / Oncology / Papillomaviridae / Papillomavirus E7 Proteins - physiology / Papillomavirus infections / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - physiology / Repressor Proteins - physiology / Signal Transduction - genetics / Squamous cell carcinoma / Transcription / Tumor cell lines / Tumorigenesis / Tumors / Up-Regulation - genetics / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - pathology