Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

Su, D.; Wang, W.; Hou, Y.; Wang, L.; Wang, Y.; Yang, C.; Liu, B.; Chen, X.; Wu, X.; Wu, J.; Yan, D.; Wei, S.; Han, L.; Liu, S.; Shi, L.; Shan, L.

doi:10.1101/641977

bioRxiv · 10.1101/641977

Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

Su, D.·Wang, W.·Hou, Y.·Wang, L.·Wang, Y.·Yang, C.·Liu, B.·Chen, X.·Wu, X.·Wu, J.·Yan, D.·Wei, S.·Han, L.·Liu, S.·Shi, L.·Shan, L.

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Abstract

Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in melanoma cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives melanoma cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during melanoma progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of melanoma patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for melanoma.

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Su, D., Wang, W., Hou, Y., Wang, L., Wang, Y., Yang, C., Liu, B., Chen, X., Wu, X., Wu, J., Yan, D., Wei, S., Han, L., Liu, S., Shi, L., Shan, L.. 2019-05-18. Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis. https://doi.org/10.1101/641977

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