Abstract
ZFP36L1 is a tandem zinc-finger RNA-binding protein that recognizes conserved adenylate-uridylate-rich elements (ARE) located in 3'untranslated regions (UTR) to mediate mRNA decay. We hypothesized that ZFP36L1 is a negative regulator of a posttranscriptional hub involved in mRNA half-life regulation of cancer-related transcripts. Analysis of in silico data revealed that ZFP36L1 was significantly mutated, epigenetically silenced, and downregulated in a variety of cancers. Forced expression of ZFP36L1 in cancer cells markedly reduced cell proliferation in vitro and in vivo, whereas silencing of ZFP36L1 enhanced tumor cell growth. To identify direct downstream targets of ZFP36L1, systematic screening using RNA pull-down of wild-type and mutant ZFP36L1 as well as whole transcriptome sequencing of bladder cancer cells {plus minus} tet-on ZFP36L1 was performed. A network of 1,410 genes was identified as potential direct targets of ZFP36L1. These targets included a number of key oncogenic transcripts such as HIF1A, CCND1, and E2F1. ZFP36L1 specifically bound to the 3'UTRs of these targets for mRNA degradation, thus suppressing their expression. Dual luciferase reporter assays and RNA electrophoretic mobility shift assays showed that wild-type, but not zinc-finger mutant ZFP36L1, bound to HIF1A 3'UTR and mediated HIF1A mRNA degradation, leading to reduced expression of HIF1A and its downstream targets. Collectively, our findings reveal an indispensable role of ZFP36L1 as a posttranscriptional safeguard against aberrant hypoxic signaling and abnormal cell-cycle progression. SIGNIFICANCE: RNA-binding protein ZFP36L1 functions as a tumor suppressor by regulating the mRNA stability of a number of mRNAs involved in hypoxia and cell-cycle signaling.
Highlights
Urinary bladder cancer is one of the most frequently diagnosed cancers worldwide, with an estimate of 430,000 new cases and 160,000 deaths in 2012 [1]
Western blots were performed to examine the expression of cell motility–related genes, and the results showed that vimentin and N-cadherin were decreased in ZFP36L1-expressing cells (Fig. 2F and G; Supplementary Fig. S7H and S7I)
ZFP36L1 is a novel tumor suppressor involved in hypoxia, cell-cycle progression, angiogenesis, and metabolism
Summary
Urinary bladder cancer is one of the most frequently diagnosed cancers worldwide, with an estimate of 430,000 new cases and 160,000 deaths in 2012 [1]. Patients with superficial non-muscle–invasive bladder cancers have prolonged survival yet frequently recur In a variety of cancers, many ARE-containing transcripts have a prominent role in proliferation, metabolism, angiogenesis, and survival in adverse conditions such as hypoxia [5, 6]. AU-rich RNA-binding proteins (AUBP) bind to multimeric AUUUA sequences, leading to either stabilization or degradation of target RNA. All three ZFP36 family members contain highly conserved tandem zinc-fingers that recognize AREs sequences in 30UTRs of RNA [7,8,9]. ZFP36L1 acts as an adaptor protein and interacts with RNA degradation complexes to participate in ARE-mediated RNA decay. ZFP36L1 recruits deadenylase such as CCR4 for deadenylation and delivers deadenylated RNA transcripts to P-bodies for decapping (by DCP1a and DCP2) prior to 50-to-30 exonucleolytic decay ZFP36L1 interacts with exosome component RRP4s for 30–50 decay [10]
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