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

Abstract

BackgroundHistone 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.MethodsMYSM1 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.ResultsMYSM1 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.ConclusionsMYSM1 plays essential suppressive roles in CRC tumorigenesis and is a potential target for reducing CRC progression and distant metastasis.