Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer.

Autor: Ghate NB; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA., Kim S; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA., Shin Y; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA., Kim J; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA., Doche M; Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, 90064, USA., Valena S; Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, 90064, USA., Situ A; Department of Biochemistry and Molecular Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, 90033, USA., Kim S; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA., Rhie SK; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA., Lenz HJ; Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA., Ulmer TS; Department of Biochemistry and Molecular Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, 90033, USA., Mumenthaler SM; Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, 90064, USA., An W; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA. woojinan@usc.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 17; Vol. 14 (1), pp. 2140. Date of Electronic Publication: 2023 Apr 17.
DOI: 10.1038/s41467-023-37883-1
Abstrakt: Our recent work has shown that DCAF1 (also known as VprBP) is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether DCAF1 also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that DCAF1 phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, DCAF1-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a mechanism underlying DCAF1-driven colonic tumorigenesis by linking DCAF1-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.
(© 2023. The Author(s).)
Databáze: MEDLINE
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