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

Nikhil B. Ghate, Sungmin Kim, Yonghwan Shin, Jinman Kim, Michael Doche, Scott Valena, Alan Situ, Sangnam Kim, Suhn K. Rhie, Heinz-Josef Lenz, Tobias S. Ulmer, Shannon M. Mumenthaler and Woojin An ()
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Nikhil B. Ghate: University of Southern California
Sungmin Kim: University of Southern California
Yonghwan Shin: University of Southern California
Jinman Kim: University of Southern California
Michael Doche: University of Southern California
Scott Valena: University of Southern California
Alan Situ: University of Southern California
Sangnam Kim: University of Southern California
Suhn K. Rhie: University of Southern California
Heinz-Josef Lenz: University of Southern California
Tobias S. Ulmer: University of Southern California
Shannon M. Mumenthaler: University of Southern California
Woojin An: University of Southern California

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37883-1

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