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RNA Biology Centre Meeting – 26 Feb
Venue: Level 12 Conference Room
Scientific work presentation:
Speaker: Xin Yi LOH (Prof H. Phillip Koeffler’s group)
Title: ZFP36L1 suppresses hypoxia and cell cycle signaling
ZFP36L1 is a tandem zinc-finger RNA binding protein (RBP) that recognizes conserved Adenylate-Uridylate-rich elements (AU-rich elements, AREs) located in 3’untranslated regions (UTRs) mediating mRNAs decay process. Here, we hypothesized that ZFP36L1 is a negative regulator of a post-transcriptional hub involving in mRNA half-life regulation of cancer-related transcripts. To identify the direct downstream targets of ZFP36L1, a systematic screening using RNA pull-down and whole transcriptome sequencing of bladder cancer cells ± ZFP36L1 was performed. Analysis of in silico data revealed that ZFP36L1 is significantly mutated, epigenetically silenced and downregulated in a variety of cancers. Forced expression of ZFP36L1 in cancer cells markedly reduced in vitro and in vivo cell proliferation; whereas silencing of ZFP36L1 enhanced tumor cells growth. We identified a network of 1,410 targets, which were bound by wildtype, but not zinc finger mutant ZFP36L1. These targets included a number of key oncogenic transcripts, such as HIF-1α, CCND1 and E2F1. ZFP36L1 specifically bound to 3’UTRs of these targets for mRNA degradation, thus suppressing their mRNA and protein expressions. Dual luciferase reporter assays and RNA Electro-Mobility Shift Assays (RNA-EMSA) showed that wildtype, but not zinc finger mutant ZFP36L1, bound to HIF-1α 3’UTR and mediated HIF-1α mRNA degradation. This eventually leads to reduced expressions of HIF-1α and its downstream targets in metabolism and angiogenesis. Collectively, our findings shed light on the pathophysiology of bladder tumorigenesis and revealed an indispensable role of ZFP36L1 as a posttranscriptional safeguard against aberrant hypoxic signaling and abnormal cell cycle progression.