Gao Wujiang, Chen Lu, Lin Li, Yang Meiling, Li Taoqiong, Wei Hong, Sha Chunli, Xing Jie, Zhang Mengxue, Zhao Shijie, Chen Qi, Xu Wenlin, Li Yuefeng, Zhu Xiaolan
Reproductive Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Oncogenesis. 2022 Mar 10;11(1):13. doi: 10.1038/s41389-022-00387-6.
Chemoresistance is a severe outcome among patients with epithelial ovarian cancer (EOC) that leads to a poor prognosis. YBX-1 has been shown to cause treatment failure and cancer progression in EOC. However, strategies that directly target YBX-1 are not yet conceivable. Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain. Mechanistic studies show that YBX-1 was ubiquitinated by SIAH1 at lys304 that lead to the instability of its target m5C-modified mRNAs, thus sensitized EOC cells to cDDP. Overexpression of SIAH1 enhanced the antitumor efficacy of cisplatin in vitro and in vivo, which were partially impaired by ectopic expression of YBX-1 or depletion of YBX-1 ubiquitination. In summary, our data identify the SIAH1/YBX-1 interaction as a therapeutic target for overcoming EOC chemoresistance.
化疗耐药是上皮性卵巢癌（EOC）患者的一个严重后果，会导致预后不良。YBX-1已被证明会导致EOC的治疗失败和癌症进展。然而，直接靶向YBX-1的策略目前还不可行。在此，我们发现，在化疗耐药的EOC样本和细胞系中表达下调的SIAH1作为一种新的E3连接酶，通过其环状结构域在细胞质中触发YBX-1的降解。机制研究表明，YBX-1在赖氨酸304位点被SIAH1泛素化，导致其靶标m5C修饰的mRNA不稳定，从而使EOC细胞对顺铂敏感。SIAH1的过表达增强了顺铂在体外和体内的抗肿瘤疗效，而YBX-1的异位表达或YBX-1泛素化的缺失则部分削弱了这种疗效。总之，我们的数据确定了SIAH1/YBX-1相互作用是克服EOC化疗耐药的一个治疗靶点。
