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HPVE6-USP46 Mediated Cdt2 Stabilization Reduces Set8 Mediated H4K20-Methylation to Induce Gene Expression Changes
Shashi Kiran1,2, Briana Wilson1, Shekhar Saha1
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
Cancers
|January 11, 2022
Summary
High-risk HPV E6 protein stabilizes Cdt2 by activating USP46, leading to Set8 degradation and altered gene expression in cervical cancer cells.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- High-risk human papillomavirus (HPV) E6 protein is a known oncogene that deregulates p53.
- Previous work showed HPV E6 recruits USP46 to Cdt2, stabilizing Cdt2 and promoting tumor growth.
Purpose of the Study:
- To elucidate the mechanism by which HPV E6 stabilizes Cdt2.
- To investigate the downstream consequences of Cdt2 stabilization on gene expression and protein levels in HPV-induced cancers.
Main Methods:
- Immunohistochemistry on cervical cancer biopsies.
- In vitro studies using HPV-transformed cell lines with gene knockdown.
- Biochemical assays with purified E6:USP46 complex.
- Deletion mapping of Cdt2 protein.
Main Results:
- Cervical cancer biopsies show decreased Set8 and H4K20 methylation, correlating with Cdt2 stabilization.
- HPV E6 directly activates USP46's deubiquitinase activity, stabilizing Cdt2 independently of UAF1 and WDR20.
- Specific regions of Cdt2 are essential for E6:USP46-mediated stabilization.
- E6 knockdown in cell lines increases Set8 and alters EGFR-related gene expression.
Conclusions:
- HPV E6 activates USP46 to stabilize Cdt2, leading to Set8 degradation and altered gene expression in HPV-transformed cells.
- This mechanism contributes to the oncogenic potential of high-risk HPV.
- Targeting the E6-USP46-Cdt2 axis may offer therapeutic strategies for HPV-induced cancers.
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