ROLE OF ZFP36L1 IN CANCER PROGRESSION

Abstract

ZFP36L1 is a tandem zinc-finger RNA binding protein (RBP) that recognizes conserved Adenylate-uridylate-rich elements (AREs) located in 3’UTRs of labile mRNAs and mediates the mRNAs decay process. Forced expression of ZFP36L1 markedly reduced in vitro cellular proliferation and cell migration; whereas ZFP36L1 silencing enhanced tumor cells growth and blood vascularity formation. A list of 1,410 targets were bound and regulated by ZFP36L1, including novel targets HIF-1α, CCND1 and E2F1. Dual luciferase reporter assays and RNA Electro-mobility Shift Assays (REMSA) showed that only wild type ZFP36L1, but not mutant zinc finger arms of ZFP36L1, binds to HIF-1α 3’UTR and mediates mRNA degradation. In addition, ZFP36L1 suppresses a myriad of key cell cycle mediators, e.g. Cyclin D1, Cyclin D3, CDK2 and E2F1, in an ARE-dependent manner. Collectively, our findings revealed a critical role of ZFP36L1 as a posttranscriptional safeguard against aberrant hypoxic signaling and cell cycle progression during tumorigenesis.