癌症研究
重编程
肝细胞癌
转录因子
索拉非尼
酪氨酸激酶
激酶
野生型
生物
化学
信号转导
细胞生物学
突变体
生物化学
细胞
基因
作者
Zhiwen Ding,Yu-Fei Pan,Taiyu Shang,Tianyi Jiang,Yun-Kai Lin,Chun Yang,Shujie Pang,Xiaowen Cui,Yixiu Wang,Xiaofan Feng,Mengyou Xu,Mengmiao Pei,Yibin Chen,Xin Li,Jin Ding,Ye-Xiong Tan,Hongyang Wang,Lixue Dong,Lu Wang
标识
DOI:10.1038/s41467-023-41852-z
摘要
Abstract The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 ( SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.
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