Sohlh2 Regulates the Stemness and Differentiation of Colon Cancer Stem Cells by Downregulating LncRNA-H19 Transcription

Abstract

Abstract Colon cancer stem cells (CSC) are tumor-initiating cells that drive tumorigenesis and progression through self-renewal and various differentiation potency. Therefore, the identification of factors critical for colon CSC function is vital for the development of therapies. Sohlh2 belongs to the superfamily of bhlh transcription factors and serves as a tumor suppressor in several tumors. The role of Sohlh2 in CSCs remains unknown. Here we demonstrated that Sohlh2 was related to the inhibition of LncRNA-H19/miR-141/β-catenin signaling and led to the consequent suppression of colon CSC stemness and the promotion of colon CSC differentiation in vitro and in vivo. Moreover, Sohlh2 could directly bind to the promoter of LncRNA-H19 and repress its transcription activity. LncRNA-H19 mediated the effects of Sohlh2 on colon CSC stemness and differentiation. Clinically, we observed a significant inverse correlation between Sohlh2 and LncRNA-H19, β-catenin, Lgr5, CD133 expression levels, and positive correlation between Sohlh2 and MUC2, TFF2 expression in colon cancer tissues. Collectively, our findings suggest an important role of the Sohlh2/LncRNA-H19/miR-141/β-catenin pathway in regulating colon CSC stemness and differentiation, suggesting potential therapeutic targets for colon cancer. Implications: This study identifies that Sohlh2 directly manipulates LncRNA-H19 transcription and suppresses the β-catenin signaling pathway and the Sohlh2/LncRNA-H19/miR-141/β-catenin signaling pathway plays an essential role in the stemness of colon CSCs.