Role of RhoC in regulation of stemness in Cervical Carcinoma

Abstract

Cancer stem cells (CSCs) have been implicated in therapy resistance, and their sensitization is critical to achieve good prognosis. This work provides mechanistic insight into RHOC-mediated regulation of cervical CSCs. Using both cell lines and clinical specimens, it is elucidated that RHOC imparts stem-like ability by up-regulating the expression of stemness genes such as Nanog and CD49f. RHOC was found to activate ERK signalling, resulting in nuclear localization of E2F, leading to increased expression of stemness genes, like CD49f and ALDH. In the nucleus, RHOC was observed to promote DNA hypomethylation by TET2 over-expression. Mechanistically, RHOC interacted with WDR5 and increased H3K4me3 levels, resulting in activation of pluripotency genes, particularly Nanog, eventually yielding an epigenetically altered “hyper-transcriptional” cell. Overall, this work elucidates that RHOC regulates the stemness phenotype by a two-pronged mechanism, comprising of both cytosolic and nuclear means. These data cumulatively highlight the potential use of RHOC as a biomarker to predict CSC load, and positions it, along with TET2 and WDR5, as potential therapeutic targets to improve clinical outcomes.