Tumor‐suppressive miR‐145 co‐repressed by TCF4‐β‐catenin and PRC2 complexes forms double‐negative regulation loops with its negative regulators in colorectal cancer. Issue 2 (3rd October 2017)

• Record Type: Journal Article
• Authors: Wang, Wei; Xiao, Xin; Chen, Xu; Huo, Yi; Xi, Wen‐Jin; Lin, Zhi‐Feng; Zhang, Dan; Li, Yu‐Fang; Yang, Fan; Wen, Wei‐Hong; Yang, An‐Gang; Wang, Tao
• Is Part Of: International journal of cancer. Volume 142:Issue 2(2018)
• Page Start: 308
• Page End: 321
• Publication Date: 2017-10-03
• Subjects: colorectal cancer -- Wnt signaling -- histone trimethylation -- tumor‐suppressive miRNA; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31056
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : The frequently dysregulated Wnt/β‐catenin signaling in different malignancies, by activation of its own or orchestration with other co‐factors, regulates various oncogenic or tumor‐suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt‐induced oncogenic miRNAs, the specific mechanism underlying the Wnt‐repressed tumor‐suppressive miRNAs is much less understood. In our study, firstly by analyzing a ChIP‐seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor‐suppressive miRNAs potentially regulated by Wnt signaling. Then through siRNA‐mediated knock‐down tests and protein and chromatin immunoprecipitations, we found the TCF4‐β‐catenin complex can recruit the histone trimethylation complex PRC2 as a co‐repressor while binding to the TCF4‐binding element (TBE) in the promoter regions of miR‐145, miR‐132 and miR‐212. Thus, upon Wnt signaling activation, the PRC2‐mediated trimethylation of histone H3 at lysine 27 increases at these promoter regions, leading to decreased miRNA levels. Furthermore, we found that by targeting TCF4 and SUZ12, the key components of the negative regulation complexes, the tumor‐suppressive miR‐145 co‐repressed by Wnt signaling and histone trimethylation, forms double‐negative regulation loops with its negative regulators in CRC cells. And the inverse associations between miR‐145 and its targets/negative regulators have also been demonstrated in nude mice and clinical samples. Collectively, we elucidated the detailed molecular mechanism of how dysregulated Wnt/β‐catenin signaling and tumor‐suppressive miRNAs reciprocally regulate each other in CRC cells. Abstract : What's new? Various dysfunctions of the Wnt signaling pathway crop up in many different cancers. These authors set out to reveal in detail how Wnt signaling molecules disable tumor suppressing microRNAs, specifically in colorectal cancer cells. They discovered that TCF4‐β‐catenin complexes can bind to the sequences in the miRNA‐145 promoter, then recruit the histone trimethylase PRC2. When activated by Wnt, PRC2 methylates the promoter and slows production of miRNA‐145. For its part, miRNA‐145 targets TCF4, thus inhibits the molecules that suppress it in a double‐negative feedback loop. The authors verified these interactions in mice, as well as in human tumor samples.