EZH2 regulates H2B phosphorylation and elevates colon cancer cell autophagy

Abstract

Epigenetic alterations, especially histone modification, play vital roles in the pathogenesis of colon cancer. Upregulation of the enhancer of zeste homolog 2 (EZH2) has been reported to contribute to the initiation and progression of colon cancer. This study analyzed the association between EZH2 and phosphorylation of H2B at tyrosine 37 (H2B^Y37ph ) in colon cancer tissues and cells, along with the influences of the EZH2-H2B^Y37ph axis on colon cancer cell autophagy. Immunohistochemistry was utilized to assess EZH2 and H2B^Y37ph expressions in clinical samples of colon cancer. Cell transfection was carried out to alter EZH2 and H2B^Y37ph expressions in colon cancer cells. Co-immunoprecipitation analysis and glutathione-S-transferase (GST) pull down assay were conducted to analyze the association between EZH2 and H2B^Y37ph . Western blotting was utilized to measure proteins expressions related to cell autophagy. We found that there was a positive association between EZH2 and H2B^Y37ph in colon cancer tissues and cells. EZH2 directly interacted with H2B and promoted H2B^Y37ph in colon cancer cells using ATP as a phosphate donor. Moreover, EZH2 levated colon cancer cell autophagy in starvation condition. H2B^Y37ph was required for EZH2-elevated colon cancer cell autophagy under starvation condition. The EZH2-H2B^Y37ph axis elevated colon cancer cell autophagy possibly via activating transcriptional regulation of ATG genes. In conclusion, EZH2-elevated colon cancer initiation and progression at least in part via inducing colon cancer cell autophagy. EZH2 could phosphorylate H2B^Y37 and then induce transcription activation of ATG genes in colon cancer cells under starvation condition.

Keywords: ATG genes; EZH2; cell autophagy; colon cancer; histone phosphorylation.