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Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA Purpose: This aim of study was to investigate the clinicopathologic significance and potential role of histone methyltransferase SET8 in the progression of gastric carcinoma (GC). Experimental Design: SET8 was screened out by gene microarray in gastric cell lines with or without miR-192/-215 inhibitors or mimics. The effects of SET8 on cell proliferation, invasion, and metastasis were examined using EdU assays, invasion studies, subcutaneous tumor experiments, and tail-vein injection in nude mice. Immunohistochemical staining was performed to detect SET8 expression in GC tissues, and real-time PCR was performed to examine the correlations between miR-192/-215 and SET8. SA-β-Gal staining assays were performed to identify the occurrence of senescence. Senescence-associated proteins were examined by real-time PCR and Western blotting. Results: SET8 regulated by miR-192/-215 displayed decreased expression in GC. Inhibition of miR-192/-215 resulted in weakened proliferation, migration, and invasion in GC. The 3'UTR of SET8 was targeted by miR-192/-215, and SET8 siRNA treatment successfully rescued the biological phenomenon. SET8 was found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro , highlighting the functional mechanism of the miR-192/-215/SET8 axis in GC. During OIS, p53 and p21 were key genetic switch points. Taken together, these data show that the miR-192/-215/SET8/p53 circuit is a key regulator of GC promotion and is highly associated with proliferation, migration, and metastasis. Conclusions: Our findings reveal that SET8 functions via the OIS-signaling pathway as a negative regulator of metastasis. This provides an experimental rationale for investigation of the OIS-signaling pathway as a potential therapeutic target in GC. Supported by : National Nature Science Foundation of China (81772592) to Z.J.; National Nature Science Foundation of China (81871969) to X.Z.; National Natural Youth Science Foundation of China (31601028) to Y.P.; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases (2019B030301009) to Z.J. Citation Format: Xiaojing Zhang, Yin Peng, Fan Hu, Yuli Gao, Jin Zhe, Stephenj Meltzer. Histone methyltransferase SET8 is regulated by miR-192/-215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3834.