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Abstract：
Prostate cancer is a disease that depends on androgenic stimulation and is thus commonly treated with androgen deprivation therapy (ADT). ADT is highly successful initially; however, patients inevitably relapse at which point the cancer grows independently of androgens and is termed castration-resistant prostate cancer (CRPC). CRPC develops through various mechanisms, one of these being crosstalk of the androgen receptor (AR) signaling pathway with other signaling pathways. Congruently, prior work has shown that androgen deprivation induces SHH signaling, which subsequently promotes activation of AR-dependent gene expression to promote cell growth. Mechanistically, this crosstalk involves a physical interaction between AR and components of SHH signaling, specifically proteins of the GLI transcription factor family. These findings thus suggest that activation of SHH signaling could promote the recurrence of cell growth in the absence of androgens to ultimately lead to progression towards CRPC. In this study, we have investigated this mechanism in a subset of prostate cancer that harbors genetic alterations within the Mediator subunit 12 (MED12). We found that loss of MED12 promotes the expression of GLI3 target genes which subsequently drives excessive cell growth in the absence of androgens. Thus, we conclude that genetic alterations within MED12 promote CRPC through hyperactivated GLI3 dependent sonic hedgehog signaling.
摘要：
前列腺癌是一种依赖于雄激素刺激的疾病，因此通常用雄激素剥夺疗法（ADT）治疗。ADT最初非常成功；然而，患者不可避免地复发,此时癌症的生长与雄激素无关,被称为去势抵抗性前列腺癌(CRPC).CRPC通过各种机制发展，其中之一是雄激素受体（AR）信号通路与其他信号通路的串扰。一致地，先前的工作表明，雄激素剥夺诱导SHH信号，随后促进AR依赖性基因表达的激活以促进细胞生长。机械上,这种串扰涉及AR和SHH信号分量之间的物理相互作用，特别是GLI转录因子家族的蛋白质。因此，这些发现表明，SHH信号的激活可以在缺乏雄激素的情况下促进细胞生长的复发，最终导致向CRPC的进展。在这项研究中,我们已经在一个在Mediator亚基12(MED12)内具有遗传改变的前列腺癌子集中研究了这一机制.我们发现MED12的缺失促进GLI3靶基因的表达,其随后在不存在雄激素的情况下驱动细胞过度生长。因此，我们得出的结论是，MED12内的遗传改变通过过度激活的GLI3依赖的Sonichedgehog信号促进CRPC。
