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Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression,making it an invaluable target for epigenetic cancer therapy.Disrupting the EZH2-EED interaction,which is required for PRC2 enzymatic activity,is a promising strategy for cancer treatment.However,this kind of inhibitors are still limited.The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology.Co-immunoprecipitation (Co-IP),protein thermal shift assay (PTSA),and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291.The anti-tumor effects of AZD9291 on breast cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected.MicroRNA array assay,luciferase reporter assay,and qRT-PCR were conducted to identify the interaction and regulation among AZD9291,EZH2,and miR-34a.We discovered that,AZD9291,a potent and selective EGFR inhibitor,disrupted the interaction of EZH2-EED,leading to impairment of PRC2 activity and downregulation of EZH2 protein.In addition,AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor,miR-34a.Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.