Epigenetic Suppression of miR-137 Induces RNF4 Expression, Facilitating Wnt Signaling in Colorectal Cancer

Yazhou Wu; Hanhua Li; Yin Long; Zhenzhen Zhang; Fanping Zhang; Runyu Pan; Leijun Meng; Zhan Ma; Kaijing Wang; Bing Zheng; Zhonghong Qie; Wei Gao

doi:10.1002/mc.23859

Epigenetic Suppression of miR-137 Induces RNF4 Expression, Facilitating Wnt Signaling in Colorectal Cancer

Mol Carcinog. 2024 Dec 4. doi: 10.1002/mc.23859. Online ahead of print.

Authors

Yazhou Wu^{1

2

3

4

5}, Hanhua Li^{1

3

4

5}, Yin Long^{5

6}, Zhenzhen Zhang⁵, Fanping Zhang⁵, Runyu Pan^{1

3

4}, Leijun Meng^{1

3

4}, Zhan Ma^{1

3

4}, Kaijing Wang⁷, Bing Zheng², Zhonghong Qie⁸, Wei Gao⁹

Affiliations

¹ Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Laboratory Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Clinical Laboratory, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
⁶ Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Hepatobiliary Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
⁸ Department of Clinical Laboratory, Shanghai health and medical center, Wuxi, China.
⁹ Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

PMID: 39630054
DOI: 10.1002/mc.23859

Abstract

Colorectal cancer (CRC) is a significant health issue worldwide. Recent studies highlight the critical role of miRNAs in CRC development, particularly miR-137, which acts as a key tumor suppressor. Despite its known role, further exploration of miR-137's downstream signaling is needed to understand its biology and therapeutic potential. We examined the methylation status of miR-137 using one TCGA data and three GEO data sets. A clinical validation cohort of 78 samples was analyzed using MSP for miR-137 promoter methylation. Various in vitro molecular/cellular and animal experiments were conducted to elucidate miR-137's role in CRC. Bioinformatic analysis indicated frequent methylation of miR-137 in CRC tissues, correlating with suppressed expression. EZH2-mediated H3K27 trimethylation silences miR-137 in CRC cells by increasing chromatin compaction, reversible by EZH2 siRNA or inhibitor GSK343. miR-137 inhibits CRC cell proliferation, migration, invasion, and xenograft tumor growth, confirming its tumor-suppressive role. Using the miRWalk repository showed that miR-137 regulates the Wnt signaling pathway by reducing typical protein expression in HCT116 and SW480 cells. miR-137 directly targets RNF4, leading to its downregulation at transcriptional and protein levels, with an observed inverse correlation in CRC tissues. miR-137 accelerates c-Myc and β-catenin degradation by inhibiting RNF4, impacting protein stability and Wnt pathway inhibition. miR-137 is epigenetically silenced through DNA methylation and EZH2-mediated H3K27 trimethylation. It regulates the Wnt signaling pathway by targeting RNF4, leading to c-Myc and β-catenin destabilization. Restoring miR-137 or inhibiting RNF4 suppresses CRC cell proliferation, migration, invasion, and tumor growth, highlighting its therapeutic potential in CRC.

Keywords: RNF4; Wnt signaling pathway; colorectal cancer; epigenetic silencing; miR‐137.

Grants and funding

This study was supported by Shanghai Municipal Health Commission (Grant No. 20204Y0134 to H.L.) and Zhong Nanshan Medical Foundation of Guangdong Province (Grant No. ZNSXS-20220007 to B.Z.).