肝细胞癌（HCC）是一种在世界范围内发生的恶性肿瘤，通常与不良预后相关。对索拉非尼等靶向治疗产生耐药性是临床癌症治疗的主要挑战。本研究发现10-11易位蛋白1（TET1）在索拉非尼耐药的HCC细胞中高表达，敲低TET1可以显着提高索拉非尼对HCC的治疗效果，表明TET1在索拉非尼中潜在的重要作用HCC 中的耐药性。机制研究确定，TET1 和 Yes 相关蛋白 1 (YAP1) 协同调节索拉非尼耐药 HCC 细胞中 DNA 修复相关基因的启动子甲基化和基因表达。 RNA 测序表明 DNA 损伤修复信号的激活被 TET1 抑制剂 Bobcat339 广泛抑制。我们还通过索拉非尼耐药 HCC 细胞中的启动子分析和染色质免疫沉淀测定，确定 TET1 是 YAP1 的直接转录靶标。此外，我们还表明，Bobcat339 可以克服索拉非尼耐药性，并与索拉非尼协同诱导 HCC 细胞和小鼠模型中的肿瘤根除。最后，免疫染色显示临床样本中TET1和YAP1呈正相关。我们的研究结果发现了一种以前未被认识的 HCC 索拉非尼耐药性分子途径，从而揭示了一种有前景的癌症治疗策略。© 2024。作者。

Hepatocellular carcinoma (HCC) is a malignancy that occurs worldwide and is generally associated with poor prognosis. The development of resistance to targeted therapies such as sorafenib is a major challenge in clinical cancer treatment. In the present study, Ten-eleven translocation protein 1 (TET1) was found to be highly expressed in sorafenib-resistant HCC cells and knockdown of TET1 can substantially improve the therapeutic effect of sorafenib on HCC, indicating the potential important roles of TET1 in sorafenib resistance in HCC. Mechanistic studies determined that TET1 and Yes-associated protein 1 (YAP1) synergistically regulate the promoter methylation and gene expression of DNA repair-related genes in sorafenib-resistant HCC cells. RNA sequencing indicated the activation of DNA damage repair signaling was extensively suppressed by the TET1 inhibitor Bobcat339. We also identified TET1 as a direct transcriptional target of YAP1 by promoter analysis and chromatin-immunoprecipitation assays in sorafenib-resistant HCC cells. Furthermore, we showed that Bobcat339 can overcome sorafenib resistance and synergized with sorafenib to induce tumor eradication in HCC cells and mouse models. Finally, immunostaining showed a positive correlation between TET1 and YAP1 in clinical samples. Our findings have identified a previously unrecognized molecular pathway underlying HCC sorafenib resistance, thus revealing a promising strategy for cancer therapy.© 2024. The Author(s).