RNA-Binding Protein ZFP36L1 Suppresses Hypoxia and Cell-Cycle Signaling
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 15, 2020
- Source ID
- 10.1158/0008-5472.can-18-2796
Entities
People
- Anand Mayakonda
- Angele Pei-fern Koh
- Benjamin P. Berman
- De-chen Lin
- H. Phillip Koeffler
- Henry Yang
- Jin-fen Xiao
- Jonathan W. Said
- Ling-Wen Ding
- Mei-shi Yeo
- Nachiyappan Venkatachalam
- Ngan B. Doan
- Pavithra Shyamsunder
- Pushkar Dakle
- Qiao-yang Sun
- Ruby Yun-ju Huang
- Si-qin Zhou
- Soo-Yong Tan
- Tiago C Silva
- Xin-yi Loh
- Xue-bin Ran
Organizations
- Cedars-Sinai Medical Center
- Hadassah Medical Center
- National Research Foundation
- Naval Medical Research Center
- UCLA Ronald Reagan Medical Center
- United States Army Medical Research and Development Command
- University of São Paulo