PMID- 31647887 OWN - NLM STAT- MEDLINE DCOM- 20200626 LR - 20230422 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 33 IP - 12 DP - 2019 Dec TI - G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR. PG - 14036-14050 LID - 10.1096/fj.201900233RR [doi] AB - 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. FAU - Yin, Chao AU - Yin C AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Ke, Xiaoxue AU - Ke X AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Zhang, Rui AU - Zhang R AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Hou, Jianbing AU - Hou J AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Dong, Zhen AU - Dong Z AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Wang, Feng AU - Wang F AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Zhang, Kui AU - Zhang K AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Zhong, Xi AU - Zhong X AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Yang, Liqun AU - Yang L AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. FAU - Cui, Hongjuan AU - Cui H AD - State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Chongqing, China. AD - Cancer Center, Medical Research Institute, Southwest University, Chongqing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191024 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Azepines) RN - 0 (BIX 01294) RN - 0 (Histocompatibility Antigens) RN - 0 (Histones) RN - 0 (Quinazolines) RN - EC 2.1.1.43 (EHMT2 protein, human) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM EIN - FASEB J. 2023 May;37(5):e22907. PMID: 37086100 MH - Animals MH - Autophagy MH - Azepines/pharmacology MH - Cell Cycle/drug effects/physiology MH - Cell Line MH - Cell Proliferation MH - Cell Survival/drug effects/physiology MH - Down-Regulation MH - Female MH - Histocompatibility Antigens/genetics/*metabolism MH - Histone-Lysine N-Methyltransferase/antagonists & inhibitors/genetics/*metabolism MH - Histones/metabolism MH - Humans MH - Mice, SCID MH - Neoplasms, Experimental MH - Quinazolines/pharmacology MH - Stomach Neoplasms/*metabolism MH - TOR Serine-Threonine Kinases/genetics/*metabolism EDAT- 2019/10/28 06:00 MHDA- 2020/06/27 06:00 CRDT- 2019/10/25 06:00 PHST- 2019/10/28 06:00 [pubmed] PHST- 2020/06/27 06:00 [medline] PHST- 2019/10/25 06:00 [entrez] AID - 10.1096/fj.201900233RR [doi] PST - ppublish SO - FASEB J. 2019 Dec;33(12):14036-14050. doi: 10.1096/fj.201900233RR. Epub 2019 Oct 24.