CRL4, a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in ovarian cancers. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. Here, we show that CRL4 is considerably increased in cisplatin-resistant ovarian cancer cells, and CRL4 knockdown with shRNAs is able to reverse cisplatin-resistance of ovarian cancer cells. Moreover, CRL4 knockdown markedly inhibits the expression of BIRC3, one of the inhibitors of apoptosis proteins (IAPs). Besides, lower expression level of BIRC3 is associated with better prognosis of ovarian cancer patients, and BIRC3 knockdown in ovarian cancer cells can recover their sensitivity to cisplatin. More importantly, we demonstrate that CRL4 regulates BIRC3 expression by mediating the STAT3, but not the PI3K pathway. Therefore, our results identified CRL4 as an important factor in ovarian cancer chemoresistance, suggesting that CRL4 and BIRC3 may serve as novel therapeutic targets for relapsed patients after treatment with cisplatin and its derivative to overcome the bottle neck of ovarian cancer chemoresistance.

CRL4 是一种定义明确的 E3 连接酶，据报道它被上调，并被认为是卵巢癌的潜在药物靶点。然而，CRL4的生物学功能和调节癌症化学抗性的潜在机制仍然很大程度上难以捉摸。在这里，我们显示 CRL4 在顺铂耐药的卵巢癌细胞中显着增加，并且用 shRNA 敲低 CRL4 能够逆转卵巢癌细胞的顺铂耐药。此外，CRL4 敲低显着抑制 BIRC3 的表达，BIRC3 是凋亡蛋白 (IAP) 的抑制剂之一。此外，BIRC3的低表达水平与卵巢癌患者预后较好相关，卵巢癌细胞中BIRC3的敲低可以恢复其对顺铂的敏感性。更重要的是，我们证明 CRL4 通过介导 STAT3 而不是 PI3K 途径来调节 BIRC3 的表达。因此，我们的研究结果将 CRL4 确定为卵巢癌化疗耐药的重要因素，表明 CRL4 和 BIRC3 可作为顺铂及其衍生物治疗后复发患者的新治疗靶点，以克服卵巢癌化疗耐药的瓶颈。