TMPRSS2-ERG gene fusion occurs in approximately 50% of cases of prostate cancer (PCa), and the fusion product is a key driver of prostate oncogenesis. However, how to leverage cellular signaling to ablate TMPRSS2-ERG oncoprotein for PCa treatment remains elusive. Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. The dual phosphorylation triggers ERG recognition and degradation by the E3 ubiquitin ligase FBW7 in a manner independent of a canonical degron. DNA damage-induced TMPRSS2-ERG degradation was abolished by cancer-associated PTEN deletion or GSK3β inactivation. Blockade of DNA damage-induced TMPRSS2-ERG oncoprotein degradation causes chemotherapy-resistant growth of fusion-positive PCa cells in culture and in mice. Our findings uncover a previously unrecognized TMPRSS2-ERG protein destruction mechanism and demonstrate that intact PTEN and GSK3β signaling are essential for effective targeting of ERG protein by genotoxic therapeutics in fusion-positive PCa.

TMPRSS2-ERG基因融合发生在大约50％的前列腺癌（PCa）病例中，并且融合产物是前列腺癌发生的关键驱动力。但是，如何利用细胞信号消融TMPRSS2-ERG癌蛋白来治疗PCa仍然难以捉摸。在这里，我们证明DNA损伤分别通过GSK3β和WEE1介导的ERG苏氨酸187和酪氨酸190磷酸化诱导野生型ERG和TMPRSS2-ERG癌蛋白的蛋白酶体降解。双重磷酸化以独立于规范德格隆的方式触发E3泛素连接酶FBW7的ERG识别和降解。与癌症相关的PTEN缺失或GSK3β失活消除了DNA损伤诱导的TMPRSS2-ERG降解。DNA损伤诱导的TMPRSS2-ERG癌蛋白降解的阻断导致培养物和小鼠中融合阳性PCa细胞的化疗耐药性生长。我们的发现揭示了以前无法识别的TMPRSS2-ERG蛋白破坏机制，并证明完整的PTEN和GSK3β信号对于遗传阳性疗法在融合阳性PCa中有效靶向ERG蛋白至关重要。