RNA-binding protein ZFP36L1 suppresses hypoxia and cell-cycle signaling

Xin Yi Loh, Qiao Yang Sun, Ling Wen Ding*, Anand Mayakonda, Nachiyappan Venkatachalam, Mei Shi Yeo, Tiago C. Silva, Jin Fen Xiao, Ngan B. Doan, Jonathan W. Said, Xue Bin Ran, Si Qin Zhou, Pushkar Dakle, Pavithra Shyamsunder, Angele Pei Fern Koh, Ruby Yun Ju Huang, Benjamin P. Berman, Soo Yong Tan, Henry Yang, De Chen LinH. Phillip Koeffler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

ZFP36L1 is a tandem zinc-finger RNA-binding protein that recognizes conserved adenylate-uridylate–rich elements (ARE) located in 30untranslated 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 30UTRs 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 30UTR 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.

Original languageAmerican English
Pages (from-to)219-233
Number of pages15
JournalCancer Research
Volume80
Issue number2
DOIs
StatePublished - 15 Jan 2020

Bibliographical note

Publisher Copyright:
©2019 American Association for Cancer Research.

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