Characterizing and targeting PRMT5 in autophagy for cancer treatment

点击翻译按钮获取中文摘要

Abstract Breast cancer (BC) is the most diagnosed cancer and the second leading cause of cancer death in American women. Triple negative breast cancer (TNBC) accounts for 15% to 20% of all BC cases and has the worst prognosis and overall survival. Although many targeted agents are ongoing clinical trials, none have significantly improved the survival in TNBC patients. Thus, the identification of novel targets and effective strategies, including combination therapies, are urgent needed for TNBC patients. PRMT5 is emerging as a potential therapeutic target. Several PRMT5 inhibitors have been developed and are currently being evaluated in clinical trials, including a phase II trial for early-stage BC. Compared to other BC subtypes, TNBC displays the strongest PRMT5 expression. High PRMT5 expression is positively correlated with poorer survival rate in TNBC patients. Despite its association with TNBC progression, PRMT5 regulation and the molecular mechanisms by which PRMT5 promotes TNBC remain elusive. Moreover, TNBC cell lines display differential sensitivity or resistance to PRMT5 inhibitors, but the mechanisms have yet to be defined. Our preliminary studies demonstrate that: (1) PRMT5 is ubiquitinated by E3 ubiquitin ligase TRAF6, which is important for its activation and TNBC cell proliferation; (2) PRMT5 suppresses autophagy induction and catalyzes ULK1 arginine methylation; and (3) autophagy inhibition sensitizes TNBC cells to PRMT5 inhibitor. Based on these preliminary findings, we propose three aims to test our central hypothesis that TRAF6, PRMT5, and ULK1 form a novel axis to regulate autophagy and TNBC progression, and combination of PRMT5 and autophagy inhibitors is a potential strategy to combat TNBC. To validate our hypothesis, we propose three Aims. In Aim 1, we will define the mechanism through which TRAF6 regulates PRMT5 activation. In Aim 2, we will define the molecular function of PRMT5 in autophagy regulation by methylating ULK1. In Aim 3, we will evaluate the synergistic effect of PRMT5 and autophagy inhibitors in TNBC. We believe that our proposed studies will not only substantially advance current understanding of regulatory mechanism and biological function of PRMT5, but also provide a rationale for combination of PRMT5 and autophagy inhibitors to treat TNBC.