Human papillomavirus type 8 oncoproteins E6 and E7 cooperate in downregulation of the cellular checkpoint kinase‐1. Issue 3 (12th March 2019)

• Record Type: Journal Article
• Authors: Akgül, Baki; Kirschberg, Matthias; Storey, Alan; Hufbauer, Martin
• Is Part Of: International journal of cancer. Volume 145:Issue 3(2019)
• Page Start: 797
• Page End: 806
• Publication Date: 2019-03-12
• Subjects: betapapillomavirus -- HPV8 -- E6E7 -- CHK1 -- autophagy; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32223
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Human papillomavirus 8 (HPV8) is associated with the development of squamous cell carcinoma (SCC) of the skin. HPV‐infected keratinocytes are able to override normal checkpoint control mechanisms and sustain cell cycle activity, allowing for synthesis of cellular proteins necessary for viral genome amplification. To study how HPV8 may disrupt cell cycle control, we analyzed the impact of HPV8 early gene expression on one of the key regulators of cell cycle and DNA damage response, checkpoint kinase‐1 (CHK1). We found that expression of E1, E1̂E4, E2, E6 or E7 individually did not affect CHK1; however, keratinocytes expressing the complete early genome region (CER) of HPV8 showed a profound loss of CHK1 protein levels, that proved to be mediated by E6E7 co‐expression. Neither CHK1 promoter regulation nor the ubiquitin‐proteasome pathway are involved in HPV8‐mediated CHK1 repression. However, CHK1 protein repression in organotypic skin cultures was paralleled by downregulation of the autophagy marker LC3B. Treatment of HPV8‐CER expressing cells with the autophagy inhibitor Bafilomycin A1 rescued CHK1 expression and led to LC3B accumulation. Taken together, our data implicate that CHK1 autophagic degradation is enhanced by HPV8, which may contribute to the oncogenic potential of the virus. Abstract : What's new? While human papillomavirus type 8 (HPV8) is suspected of playing a role in cutaneous squamous cell carcinoma, the contributions of HPV8 to skin tumor development remain unknown. Here, expression of the complete early genome region of HPV8 was associated with a significant reduction in checkpoint kinase‐1 (CHK1) protein levels. CHK1 downregulation by HPV8 was dependent on E6E7 oncoprotein co‐expression and autophagic processes. The data demonstrate a novel oncogenic effect of HPV8 in keratinocytes, whereby CHK1 absence enables virus‐infected cells to survive in a replicative state, predisposing them to the accumulation of DNA damage from ultraviolet radiation.