Human Papillomavirus E7 Enhances Hypoxia-Inducible Factor 1–Mediated Transcription by Inhibiting Binding of Histone Deacetylases

Abstract

Infection by human papillomaviruses (HPV) leads to the formation of benign lesions, warts, and in some cases, cervical cancer. The formation of these lesions is dependent upon increased expression of proangiogenic factors. Angiogenesis is linked to tissue hypoxia through the activity of the oxygen-sensitive hypoxia-inducible factor 1a (HIF-1a). Our studies indicate that the HPV E7 protein enhances HIF-1 transcriptional activity whereas E6 functions to counteract the repressive effects of p53. Both high-and low-risk HPV E7 proteins were found to bind to HIF-1a through a domain located in the N-terminus. Importantly, the ability of E7 to enhance HIF-1 activity mapped to the C-terminus and correlated with the displacement of the histone deacetylases HDAC1, HDAC4, and HDAC7 from HIF-1a by E7. Our findings describe a novel role of the E7 oncoprotein in activating the function of a key transcription factor mediating hypoxic responses by blocking the binding of HDACs.

The E7 Open Reading Frame Acts in cis and in trans To Mediate Differentiation-Dependent Activities in the Human Papillomavirus Type 16 Life Cycle

“…Whole-cell extracts were prepared and subjected to SDS-PAGE and Western blotting as described previously (4,40). Antibodies used were glyceraldehyde-3-phosphate dehydrogenase (GAPDH; sc-47724; Santa Cruz), pRb (9309; Cell Signaling), cyclin A (C4710; Sigma), and E7 (28-0006; Invitrogen).…”

High-Risk Human Papillomaviruses Repress Constitutive Kappa Interferon Transcription via E6 To Prevent Pathogen Recognition Receptor and Antiviral-Gene Expression

“…To investigate whether the HR-HPV16, -18, and -31 regulate similar sets of ISGs, two human keratinocyte cell lines each harboring HPV16, HPV18, or HPV31 genomes (16-1, 16-2, 18-1, 18-2, 31-1, and 31-2) were used to compare the expression levels of selected genes with that in normal human keratinocytes from several different donors (4,13,25,40). Based on the published transcriptome studies and functional data for HR-HPVs, the expression levels of the ISGs IFIT1, MX1, PKR, and STAT1 were investigated (8,19,25,32,41).…”

Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

“…Усиление трансляции мРНК HIF-1a может быть результатом гиперактивированного состояния PI3K/Akt/mTOR-сигнального пути, свойственного многим типам рака, включая РШМ [66]. Становятся также известны ВПЧ-специфичные механизмы увеличения активности или количества HIF-1a [67,68]. Например, обнаружена способность белка Е7 непосредственно связываться с HIF-1a и вытеснять его из комплекса с гистондеацетилазами (HDAC1, HDAC4, HDAC7), стимулируя тем самым формирование активного транскрипционного комплекса [67].…”

“…Становятся также известны ВПЧ-специфичные механизмы увеличения активности или количества HIF-1a [67,68]. Например, обнаружена способность белка Е7 непосредственно связываться с HIF-1a и вытеснять его из комплекса с гистондеацетилазами (HDAC1, HDAC4, HDAC7), стимулируя тем самым формирование активного транскрипционного комплекса [67]. Е7-опосредованное нарушение функционирования клеточных систем убиквитинирования может являться причиной снижения скорости оборота HIF-1a и его накопления в ВПЧ-инфицированных клетках.…”