Protein kinase A-mediated phosphorylation regulates STAT3 activation and oncogenic EZH2 activity

Ali R. Özeş, Nick Pulliam, Mustafa G. Ertosun, Özlem Yllmaz, Jessica Tang, Ece Çopuroǧlu, Daniela Matei, Osman N. Özeş, Kenneth P. Nephew

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Polycomb repressive complex 2 (PRC2) member enhancer of zeste homolog 2 (EZH2) trimethylates histone H3 lysine 27 (H3K27me3), alters chromatin structure and contributes to epigenetic regulation of gene expression in normal and disease processes. Phosphorylation of EZH2 augmented EZH2 oncogenic activity in cancer but observations have been limited to threonine 350 (T350) and serine 21 (S21) residues by cyclin-dependent kinase 1 and protein kinase B, respectively. In addition, phosphorylation of the evolutionarily conserved T372 motif of EZH2 by p38 resulted in EZH2 interaction with Ying Yang 1 and promoted muscle stem cell differentiation. In the present study, we used epithelial ovarian cancer (OC) cells as a model to demonstrate that phosphorylation of EZH2 at T372 by protein kinase A (PKA) induced a dominant-negative EZH2 phenotype, inhibited OC cell proliferation and migration in vitro and decreased ovarian xenograft tumor growth in vivo. Phosphorylation of T372 by PKA enhanced the interaction between EZH2 and signal transducer and activator of transcription 3 (STAT3), and STAT3 binding to pT372-EZH2 reduced cellular levels of pSTAT3 and downregulated interleukin 6 receptor expression in OC. Furthermore, PKA-mediated pT372-EZH2 decreased ATP levels and altered mitochondrial gene expression, resulting in mitochondrial dysfunction and reduced OC cell growth. These findings demonstrate that PKA-mediated T372 phosphorylation reduces oncogenic EZH2 activity and reveal a novel role for pT372 in regulating EZH2 in OC and possibly other cancers.

Original languageEnglish (US)
Pages (from-to)3589-3600
Number of pages12
JournalOncogene
Volume37
Issue number26
DOIs
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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