RNA-Binding Protein ZFP36L1 Suppresses Hypoxia and Cell-Cycle Signaling.

Autor:	Loh XY; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Sun QY; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Ding LW; Cancer Science Institute of Singapore, National University of Singapore, Singapore. lingwen.dlw@gmail.com., Mayakonda A; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Venkatachalam N; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Yeo MS; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Silva TC; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California., Xiao JF; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Doan NB; Pathology and Laboratory Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, California., Said JW; Pathology and Laboratory Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, California., Ran XB; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Zhou SQ; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Dakle P; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Shyamsunder P; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Koh AP; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Huang RY; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Berman BP; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.; Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel., Tan SY; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Yang H; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Lin DC; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California., Koeffler HP; Cancer Science Institute of Singapore, National University of Singapore, Singapore.; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; National University Cancer Institute of Singapore, National University Hospital, Singapore.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Jan 15; Vol. 80 (2), pp. 219-233. Date of Electronic Publication: 2019 Sep 24.
DOI:	10.1158/0008-5472.CAN-18-2796
Abstrakt:	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. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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