TY - JOUR
T1 - RhoJ regulates melanoma chemoresistance by suppressing pathways that sense DNA damage
AU - Ho, Hsiang
AU - Aruri, Jayavani
AU - Kapadia, Rubina
AU - Mehr, Hootan
AU - White, Michael A.
AU - Ganesan, Anand K.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-12-0775
DO - 10.1158/0008-5472.CAN-12-0775
M3 - Article
C2 - 22971344
AN - SCOPUS:84868237298
SN - 0008-5472
VL - 72
SP - 5516
EP - 5528
JO - Cancer research
JF - Cancer research
IS - 21
ER -