PS1347 PHF19 INDUCES EZH2 PHOSPHORYLATION AND PROMOTES DRUG RESISTANCE IN MULTIPLE MYELOMA

Abstract

Background:Multiple myeloma (MM) is a plasma cell malignancy characterized by consecutive progression and increased invasion. It is becoming increasingly evident that tumor development and the acquisition of drug resistance involves the alteration of epigenetic regulation. PcG (polycomb group) proteins are key to epigenetic repression through two main complexes, PRC1 (Polycomb repressive complex 1) and PRC2. PHF19, also known as PCL3, combines with histone methyltransferase EZH2 (Enhancer of Zeste 2) and participates in the formation of PRC2 complex. Our study is the first report that depicts the role of PHF19 in the drug resistance of MM, providing new therapeutic choices for these patients.Aims:To disclose the role of PHF19 in promoting drug resistance of multiple myeloma and explore the therapeutic strategy based on the mechanism research.Methods:RNA‐seq data from 351 newly‐diagnosed patients, 44 MGUS, 12 SMM and 22 healthy plasma cells reported the role of PHF19 as an independent risk predictor for survival. We then studied the functional role of PHF19 by overexpression or shRNA knockdown in ARP1 and OCI‐My5 MM cell lines, conducting cell proliferation counting, Annexin V/7AAD assay for apoptosis, and mouse xenograft experiments. Gene expression profile was performed in ARP1 MM cell line. Western blot was used to investigate the expression of the potential targets of PHF19. Dual luciferase assay was used to reveal the relation between miR‐15a and PHF19 mRNA.Results:PHF19 was associated to high‐risk and dismal outcome of MM patients. It promoted cell growth and resistance to bortezomib both in vitro and in vivo. PHF19 activated the bypass of canonical PRC2 function by recruiting AKT to phosphorylate EZH2, which released the expression of HIF‐1α, Bcl‐xL and Mcl‐1. PI3K inhibitor LY294002 reversed the upregulation of the mentioned pro‐survival proteins. miR‐15a bound to 3’UTR of PHF19 mRNA to negatively regulate its expression.Summary/Conclusion:PHF19 is correlated to disease progression and drug resistance of MM. In vitro and in vivo experiments reveal PHF19 significantly promotes cell survival and inhibites apoptotic activity. PI3K/AKT signaling pathway is highly involved in the function of PHF19, indicating inhibition of PI3K/AKT may be an effective strategy to treat those patients with high level of PHF19.