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Star-PAP controls HPV E6 regulation of p53 and sensitizes cells to VP-16

Oncogene volume 33, pages 928–932 (2014)Cite this article

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Abstract

Cervical cancer is the most common genital malignancy and the high-risk human papillomaviruses (HPV type 16, 18 and 31, and so on) are major agents for its cause. A key switch for the onset of cervical cancers by HPVs is the cellular degradation of the tumor-suppressor p53 that is mediated by the HPV-generated E6 protein. E6 forms a complex with the E3 ubiquitin-ligase E6-associated protein (E6AP) leading to p53 degradation. The components that control E6 expression and the mechanisms for regulation of the expression in host cells remain undefined. Here we show that the nuclear noncanonical poly(A) polymerase (PAP) speckle targeted PIPKIα regulated PAP (Star-PAP) controls E6 mRNA polyadenylation and expression and modulates wild-type p53 levels as well as cell cycle profile in high-risk HPV-positive cells. In the absence of Star-PAP, treatment of cells with the chemotherapeutic drug VP-16 dramatically reduced E6 and increased p53 levels. This diminished both cell proliferation and anchorage-independent growth required for cancer progression, indicating a synergism between VP-16 treatment and the loss of Star-PAP. This identifies Star-PAP as a potential drug target for the treatment of HPV-positive cancer cells. These data provide a mechanistic basis for increasing the sensitivity and efficiency of chemotherapy in the treatment of cancers that have low levels of wild-type p53.

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Acknowledgements

We thank members of the Anderson laboratory for discussion and comments, and thank Dr Paul F Lambert’s laboratory at UW-Madison for SiHa and CaSki cell lines. This work was supported by a grant (GM051968) from the US National Institutes of Health and a Scientist Development Grant (12SDG12100035) from the American Heart Association.

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  1. Molecular and Cellular Pharmacology Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

    W Li & R A Anderson

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  1. W Li
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Correspondence to R A Anderson.

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Li, W., Anderson, R. Star-PAP controls HPV E6 regulation of p53 and sensitizes cells to VP-16. Oncogene 33, 928–932 (2014). https://doi.org/10.1038/onc.2013.14

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