MYSM1 inhibits human colorectal cancer tumorigenesis by activating miR-200 family members/CDH1 and blocking PI3K/AKT signaling

Journal of Experimental & Clinical Cancer Research

Fan Feng¹  Tao Wang²  Han Zhang²  Siyi Chen³  Wenjin Xi⁴  Yi Huo⁴  Tianze Zhang⁴  Wei Wang⁴  Angang Yang⁴  Fan Yang⁴  Xu Chen⁴  Jinjian Gao⁴  Yufang Li⁴ 

[1] Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University;Department of Medical Genetics and Developmental Biology, Fourth Military Medical University;Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California;State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University;

关键词: MYSM1;    Colorectal cancer;    EMT;    miR-200;    PI3K/AKT;   

DOI  :  10.1186/s13046-021-02106-2

来源: DOAJ

【 摘 要 】

Abstract Background Histone epigenetic modification disorder is an important predisposing factor for the occurrence and development of many cancers, including colorectal cancer (CRC). The role of MYSM1, a metalloprotease that deubiquitinates monoubiquitinated histone H2A, in colorectal cancer was identified to evaluate its potential clinical application value. Methods MYSM1 expression levels in CRC cell lines and tumor tissues were detected, and their associations with patient survival rate and clinical stage were analyzed using databases and tissue microarrays. Gain- and loss-of-function studies were performed to identify the roles of MYSM1 in CRC cell proliferation, apoptosis, cell cycle progression, epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo. ChIP, rescue assays and signal pathway verification were conducted for mechanistic study. Immunohistochemistry (IHC) was used to further assess the relationship of MYSM1 with CRC diagnosis and prognosis. Results MYSM1 was significantly downregulated and was related to the overall survival (OS) of CRC patients. MYSM1 served as a CRC suppressor by inducing apoptosis and inhibiting cell proliferation, EMT, tumorigenic potential and metastasis. Mechanistically, MYSM1 directly bound to the promoter region of miR-200/CDH1, impaired the enrichment of repressive H2AK119ub1 modification and epigenetically enhanced miR-200/CDH1 expression. Testing of paired CRC patient samples confirmed the positive regulatory relationship between MYSM1 and miR-200/CDH1. Furthermore, silencing MYSM1 stimulated PI3K/AKT signaling and promoted EMT in CRC cells. More importantly, a positive association existed between MYSM1 expression and a favorable CRC prognosis. Conclusions MYSM1 plays essential suppressive roles in CRC tumorigenesis and is a potential target for reducing CRC progression and distant metastasis.

【 授权许可】

Unknown