Small molecule targeting of RhoC‐regulated gene transcription in metastatic, undifferentiated melanoma

Abstract

Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Recent evidence implicates Rho‐activated gene transcription, mediated by the nuclear localization of the transcriptional coactivator, megakaryoblastic leukemia‐1 (MKL1), in melanoma metastasis. Here, we examine correlates of Rho expression and activity as well as markers of differentiation, migration, morphology, and tumorigenicity in a panel of human metastatic melanoma cell lines. Three melanoma lines with evidence of high Rho activity also show an aggressive and undifferentiated phenotype. These melanomas selectively overexpress RhoC but not RhoA and also have increased expression of mRNA for P75, a neural crest stem cell marker and decreased expression of melanocytic differentiation markers, MITF and TYR. To target the Rho/MKL transcriptional mechanism, we have developed a small molecule inhibitor of Rho‐regulated transcription. CCG‐203971, at low μM concentrations blocks nuclear localization of MKL, produces a more melanocyte‐like cellular morphology, decreases MKL target gene expression, and inhibits cellular migration of aggressive undifferentiated melanoma cells. These data link melanoma cell differentiation with Rho activity and support targeting the Rho/MKL transcriptional pathway as a novel approach to melanoma therapeutics. (Supported by NIH –T32‐GM007767)