Wild-type and mutated beta-catenin differently repress RND3/RHOE expression in hepatocellular carcinoma

Tumor development and progression are mainly driven by oncogenic mutations but are also regulated by physical factors, such as applied forces or microenvironment stiffness. Through its structural and transcriptional functions, beta-catenin is a key factor that acts on both aspects to promote liver tumorigenesis, leading to hepatocellular carcinoma (HCC) development. However, the mechanisms by which these two functions regulate downstream targets remain poorly understood. Herein, we describe Rnd3, also called RhoE, an atypical member of the Rho GTPase family, as a common target of both functions of beta-catenin. We previously demonstrated that RND3 expression is downregulated in HCC, which correlates with intrahepatic metastasis. Yet, a molecular understanding of how Rnd3 expression is dysregulated in cancer is largely missing. Using human HCC samples and cultured cell lines, we demonstrate that Rnd3 expression is regulated by beta-catenin pathways, regardless of their mutational status. Both the transcriptional and the structural activity of beta-catenin repress the expression of RND3. Indeed, we found that wild-type beta-catenin suppresses RND3 transcription through the Hippo pathway, whereas oncogenic beta-catenin downregulates RND3 expression through miRNA targeting its 3UTR. Rnd3 may constitute a key protein involved in the transcriptional program driven by oncogenic beta-catenin in HCC and as a mediator of the mechanosensitive response associated with cell-cell adhesion.