Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
J Exp Med. 2021 Feb 1;218(2). doi: 10.1084/jem.20201137.
Melanoma susceptibility differs significantly in male versus female populations. Low levels of androgen receptor (AR) in melanocytes of the two sexes are accompanied by heterogeneous expression at various stages of the disease. Irrespective of expression levels, genetic and pharmacological suppression of AR activity in melanoma cells blunts proliferation and induces senescence, while increased AR expression or activation exert opposite effects. AR down-modulation elicits a shared gene expression signature associated with better patient survival, related to interferon and cytokine signaling and DNA damage/repair. AR loss leads to dsDNA breakage, cytoplasmic leakage, and STING activation, with AR anchoring the DNA repair proteins Ku70/Ku80 to RNA Pol II and preventing RNA Pol II-associated DNA damage. AR down-modulation or pharmacological inhibition suppresses melanomagenesis, with increased intratumoral infiltration of macrophages and, in an immune-competent mouse model, cytotoxic T cells. AR provides an attractive target for improved management of melanoma independent of patient sex.
黑素瘤易感性在男性和女性人群中存在显著差异。两性黑素细胞中的雄激素受体 (AR) 水平较低，同时在疾病的各个阶段表达也存在异质性。无论表达水平如何，遗传和药理学抑制黑素瘤细胞中的 AR 活性都会抑制增殖并诱导衰老，而增加 AR 的表达或激活则会产生相反的效果。AR 下调会引发与患者生存更好相关的共享基因表达特征，与干扰素和细胞因子信号转导以及 DNA 损伤/修复有关。AR 缺失会导致双链 DNA 断裂、细胞质渗漏和 STING 激活，同时 AR 将 DNA 修复蛋白 Ku70/Ku80 锚定到 RNA Pol II，防止 RNA Pol II 相关的 DNA 损伤。AR 下调或药理学抑制可抑制黑素瘤发生，同时增加肿瘤内巨噬细胞浸润，在免疫功能正常的小鼠模型中还增加了细胞毒性 T 细胞。AR 为改善黑素瘤的管理提供了一个有吸引力的靶点，与患者性别无关。
Zotero 插件
