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

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.

VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation

“…Because some histone modi cations such as acetylation activates transcription, opposite to the transrepressive effects of H2AT120p, future work examining melanomagenic transcription program should also focus on the competitive action of factors depositing active histone marks against VprBP. Related, our recent investigation revealed additional role for VprBP in phosphorylating EZH2 in colon cancer cells and established another epigenetic process underlying VprBP-induced oncogenic gene silencing program [32]. While a potential involvement of VprBP-mediated EZH2 phosphorylation in melanomagenesis was not explored in the current study, stable depletion and inhibition of VprBP in melanoma cells expressing low levels of EZH2 still generated a substantial increase in melanomagenic gene transcription and cell growth rates (data not shown), lending support to the notion that the pro-melanomagenic activity of VprBP is mainly through H2AT120p at target genes.…”

S-nitrosylation of EZH2 at C329 and C700 interplay with PRC2 complex assembly, methyltransferase activity, and EZH2 stability to regulate endothelial functions

“…A very recent study demonstrated DCAF1 mediated phosphorylation of EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Such DCAF1-mediated EZH2 phosphorylation followed by nuclear localization led to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells 30 . In contrast, herein we report that S-nitrosylation of C329 residue of EZH2 caused its cytosolic localization followed by lysosomal degradation.…”

VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation

“…Because some histone modifications such as acetylation activates transcription, opposite to the trans-repressive effects of H2AT120p, future work examining melanomagenic transcription program should also focus on the competitive action of factors depositing active histone marks against VprBP. Related, our recent investigation revealed additional role for VprBP in phosphorylating EZH2 in colon cancer cells and established another epigenetic process underlying VprBP-induced oncogenic gene silencing program [ 32 ]. While a potential involvement of VprBP-mediated EZH2 phosphorylation in melanomagenesis was not explored in the current study, stable depletion and inhibition of VprBP in melanoma cells expressing low levels of EZH2 still generated a substantial increase in melanomagenic gene transcription and cell growth rates (data not shown), lending support to the notion that the pro-melanomagenic activity of VprBP is mainly through H2AT120p at target genes.…”