RhoJ regulates melanoma chemoresistance by suppressing pathways that sense DNA damage

Hsiang Ho, Jayavani Aruri, Rubina Kapadia, Hootan Mehr, Michael A. White, Anand K. Ganesan

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Melanomas resist conventional chemotherapeutics, in part, through intrinsic disrespect of apoptotic checkpoint activation. In this study, using an unbiased genome-wide RNA interference screen, we identified RhoJ and its effector PAK1, as key modulators of melanoma cell sensitivity to DNA damage.We find that RhoJ activates PAK1 in response to drug-induced DNA damage, which then uncouples ATR from its downstream effectors, ultimately resulting in a blunted DNA damage response (DDR). In addition, ATR suppression leads to the decreased phosphorylation of ATF2 and consequent increased expression of the melanocyte survival gene Sox10 resulting in a higher DDR threshold required to engage melanoma cell death. In the setting of normal melanocyte behavior, this regulatory relationship may facilitate appropriate epidermal melanization in response to UV-induced DNA damage. However, pathologic pathway activation during oncogenic transformation produces a tumor that is intrinsically resistant to chemotherapy and has the propensity to accumulate additional mutations. These findings identify DNA damage agents and pharmacologic inhibitors of RhoJ/PAK1 as novel synergistic agents that can be used to treat melanomas that are resistant to conventional chemotherapies.

Original languageEnglish (US)
Pages (from-to)5516-5528
Number of pages13
JournalCancer Research
Volume72
Issue number21
DOIs
Publication statusPublished - Nov 1 2012

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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