title: RhoJ regulates melanoma chemoresistance by suppressing pathways that sense DNA damage.
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.
authors.affiliation: Department of Dermatology, University of California at Irvine, Irvine, California 92697, USA.
authors.forename: Hsiang
authors.initials: H
authors.lastname: Ho
authors.forename: Jayavani
authors.initials: J
authors.lastname: Aruri
authors.forename: Rubina
authors.initials: R
authors.lastname: Kapadia
authors.forename: Hootan
authors.initials: H
authors.lastname: Mehr
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.forename: Anand K
authors.initials: AK
authors.lastname: Ganesan
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D057166:High-Throughput Screening Assays; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection; D054462:p21-Activated Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C515903:PAK1 protein, human; D054462:p21-Activated Kinases; C417188:RHOJ protein, human; D020741:rho GTP-Binding Proteins