G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR

As an important methyltransferase, G9a has been reported to be abnormally expressed in various human cancers and plays essential roles in tumorigenesis. However, the biologic functions and molecular mechanisms of G9a in gastric Cancer (GC) remain unclear. GC is the fifth most frequent Cancer around the world and seriously threatens human health, especially in developing countries. Here, our results showed that high expression of G9a was intensively correlated with poor prognosis and more advanced stages of GCs. Knockdown of G9a or treatment with its inhibitor, BIX01294, significantly reduced cell growth by cell cycle arrest and Autophagy. In addition, the mechanistic target of rapamycin (mTOR) was evidently decreased after G9a silencing or inhibition, and mTOR activation partially rescued the effects of cell proliferation inhibition and Autophagy induced by G9a knockdown or inhibition. Down-regulation of G9a effectively inhibited mTOR expression and tumor growth in the xenograft tumor model of GC cells. We also showed that G9a regulates mTOR and cell proliferation and Autophagy depending on its histone methylase activity. Using chromatin immunoprecipitation analysis, we found that mTOR expression was associated with promoter methylation and an enrichment for mono- and dimethylated histone 3 lys 9 (H3K9). G9a knockdown revealed an apparent decrease in H3K9 monomethylation levels, but no apparent change in H3K9 dimethylation levels at the mTOR promoter. These results indicate that G9a is a novel and promising therapeutic target for GC treatment.-Yin, C., Ke, X., Zhang, R., Hou, J., Dong, Z., Wang, F., Zhang, K., Zhong, X., Yang, L., Cui, H. G9a promotes cell proliferation and suppresses Autophagy in gastric Cancer by directly activating mTOR.