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Mol Cell. 2018 Dec 6;72(5):823-835.e5. doi: 10.1016/j.molcel.2018.09.019. Epub 2018 Nov 8.

The Deubiquitinase USP46 Is Essential for Proliferation and Tumor Growth of HPV-Transformed Cancers.

Author information

1
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
2
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: ad8q@virginia.edu.

Abstract

High-risk human papilloma viruses (HPVs) cause cervical, anal, and oropharyngeal cancers, unlike the low-risk HPVs, which cause benign lesions. E6 oncoproteins from the high-risk strains are essential for cell proliferation and transformation in HPV-induced cancers. We report that a cellular deubiquitinase, USP46, is selectively recruited by the E6 of high-risk, but not low-risk, HPV to deubiqutinate and stabilize Cdt2/DTL. Stabilization of Cdt2, a component of the CRL4Cdt2 E3 ubiquitin ligase, limits the level of Set8, an epigenetic writer, and promotes cell proliferation. USP46 is essential for the proliferation of HPV-transformed cells, but not of cells without HPV. Cdt2 is elevated in human cervical cancers and knockdown of USP46 inhibits HPV-transformed tumor growth in xenografts. Recruitment of a cellular deubiquitinase to stabilize key cellular proteins is an important activity of oncogenic E6, and the importance of E6-USP46-Cdt2-Set8 pathway in HPV-induced cancers makes USP46 a target for the therapy of such cancers.

KEYWORDS:

Cdt2; E6; HPV; USP46; cervical cancer; deubiquitinase; oncogenic virus

PMID:
30415951
PMCID:
PMC6294304
[Available on 2019-12-06]
DOI:
10.1016/j.molcel.2018.09.019

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