Pharmacological inhibition of myocardin-related transcription factor pathway blocks lung metastases of RhoC-Overexpressing melanoma

Andrew J. Haak, Kathryn M. Appleton, Erika M. Lisabeth, Sean A. Misek, Yajing Ji, Susan M. Wade, Jessica L. Bell, Cheryl E. Rockwell, Merlin Airik, Melanie A. Krook, Scott D. Larsen, Monique Verhaegen, Elizabeth R. Lawlor, Richard R. Neubig

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed smallmolecule inhibitor, CCG-203971, which at low micromolar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971-mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G1 cell-cycle arrest. In an experimental model of melanoma lung metastasis, the RhoC-overexpressing melanoma cells (SK-Mel-147) exhibited pronounced lung colonization compared with the low RhoC-expressing SK-Mel-19. Furthermore, pharmacologic inhibition of the MRTF pathway reduced both the number and size of lung metastasis resulting in a marked reduction of total lung tumor burden. These data link Rho and MRTF-mediated signaling with aggressive phenotypes and support targeting the MRTF transcriptional pathway as a novel approach to melanoma therapeutics.

Original languageEnglish (US)
Pages (from-to)193-204
Number of pages12
JournalMolecular cancer therapeutics
Volume16
Issue number1
DOIs
StatePublished - Jan 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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