Oncogenic viral protein HPV E7 up-regulates the SIRT1 longevity protein in human cervical cancer cells.
Senescence is blocked in human cervical keratinocytes infected with high risk human papillomavirus (e.g. HPV type16). Viral oncoproteins HPV E6 and HPV E7 access the cell cycle via cellular p53 and retinoblastoma proteins respectively. Previously we have shown that HPV E7, not HPV E6, is also responsible for cervical cancer cell survival (SiHa cells; HPV type16). We now present evidence that SIRT1, an aging-related NAD-dependent deacetylase, mediates HPV E7 survival function in SiHa cervical cancer cells. Moreover, HPV E7 up-regulates SIRT1 protein when expressed in primary human keratinocytes. Conversely, SIRT1 levels decrease following RNAi-mediated silencing of HPV E7 in SiHa cells. Silencing HPV E6 has no effect on SIRT1 but, as expected, causes marked accumulation of p53 protein accompanied by p53-mediated up-regulation of p21. However, p53 acetylation (K382Ac) was barely detectable. Since p53 is a known SIRT1 substrate we propose that elevated SIRT1 levels (induced by HPV E7) attenuate p53 pro-apoptotic capacity via its de-acetylation. Our discovery that HPV E7 up-regulates SIRT1 links a clinically important oncogenic virus with the multi-functional SIRT1 protein. This link may open the way for a more in-depth understanding of the process of HPV-induced malignant transformation and also of the inter-relationships between aging and cancer.
Yorkshire Cancer Research P53 Research Unit, Department of Biology, University of York, York YO105DD, UK. ajm24@york.ac.uk
Simon J
SJ
Allison
Ming
M
Jiang
Jo
J
Milner
D000107:Acetylation; D000375:Aging / Q000378:metabolism; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000502:physiology; D050725:Papillomavirus E7 Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D056564:Sirtuin 1 / Q000096:biosynthesis*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000821:virology
C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C068651:E6 protein, Human papillomavirus type 16; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1