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Oncogenic viral protein HPV E7 up-regulates the SIRT1 longevity protein in human cervical cancer cells.

Allison SJ, Jiang M, Milner J - Aging (Albany NY) (2009)

Bottom Line: 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.Our discovery that HPV E7 up-regulates SIRT1 links a clinically important oncogenic virus with the multi-functional SIRT1 protein.

View Article: PubMed Central - PubMed

Affiliation: Yorkshire Cancer Research P53 Research Unit, Department of Biology, University of York, York YO105DD, UK. ajm24@york.ac.uk

ABSTRACT
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.

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Model for the                                            respective effects of HPV E6 and HPV E7 on human cervical cancer cell                                            survival and proliferation taking into account (A) up-regulation of SIRT1                                            protein by HPV E7, (B) SIRT1-mediated de-acetylation of p53 and (C)                                            SIRT1 cervical cancer cell survival functions (see text).
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Figure 5: Model for the respective effects of HPV E6 and HPV E7 on human cervical cancer cell survival and proliferation taking into account (A) up-regulation of SIRT1 protein by HPV E7, (B) SIRT1-mediated de-acetylation of p53 and (C) SIRT1 cervical cancer cell survival functions (see text).

Mentions: Previous studies have presumed that HPV E6 is the major survival determinant in human cervical cancer and this concept has directed anti-cancer pharmaceutical research towards identification of agents that block the functions of HPV E6. This has been a reasonable presumption given that HPV E6 targets the p53 tumour suppressor protein. However, our own previous [30] and present observations indicate that up-regulation of p53 following HPV E6 silencing is not sufficient to induce apoptosis in human cervical cancer cells despite induction of cell growth arrest. HPV E7 silencing, on the other hand, induces apoptosis. Apoptosis of HPV E7-silenced SiHa cells proceeds despite the continued suppression of p53 by HPV E6 ([30,44] and Figure 5 schematic). The ability of HPV E7 to up-regulate SIRT1 expression now provides a mechanistic explanation for this effect since SIRT1 is anti-apoptotic in epithelial cancer cells (Figure 5).


Oncogenic viral protein HPV E7 up-regulates the SIRT1 longevity protein in human cervical cancer cells.

Allison SJ, Jiang M, Milner J - Aging (Albany NY) (2009)

Model for the                                            respective effects of HPV E6 and HPV E7 on human cervical cancer cell                                            survival and proliferation taking into account (A) up-regulation of SIRT1                                            protein by HPV E7, (B) SIRT1-mediated de-acetylation of p53 and (C)                                            SIRT1 cervical cancer cell survival functions (see text).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806013&req=5

Figure 5: Model for the respective effects of HPV E6 and HPV E7 on human cervical cancer cell survival and proliferation taking into account (A) up-regulation of SIRT1 protein by HPV E7, (B) SIRT1-mediated de-acetylation of p53 and (C) SIRT1 cervical cancer cell survival functions (see text).
Mentions: Previous studies have presumed that HPV E6 is the major survival determinant in human cervical cancer and this concept has directed anti-cancer pharmaceutical research towards identification of agents that block the functions of HPV E6. This has been a reasonable presumption given that HPV E6 targets the p53 tumour suppressor protein. However, our own previous [30] and present observations indicate that up-regulation of p53 following HPV E6 silencing is not sufficient to induce apoptosis in human cervical cancer cells despite induction of cell growth arrest. HPV E7 silencing, on the other hand, induces apoptosis. Apoptosis of HPV E7-silenced SiHa cells proceeds despite the continued suppression of p53 by HPV E6 ([30,44] and Figure 5 schematic). The ability of HPV E7 to up-regulate SIRT1 expression now provides a mechanistic explanation for this effect since SIRT1 is anti-apoptotic in epithelial cancer cells (Figure 5).

Bottom Line: 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.Our discovery that HPV E7 up-regulates SIRT1 links a clinically important oncogenic virus with the multi-functional SIRT1 protein.

View Article: PubMed Central - PubMed

Affiliation: Yorkshire Cancer Research P53 Research Unit, Department of Biology, University of York, York YO105DD, UK. ajm24@york.ac.uk

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus