CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway
CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway
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基于 CRISPR-Cas9 的全基因组筛选确定了治疗索拉非尼耐药性肝细胞癌的新靶点：FGF21 和 NRF2 通路之间的串扰
DOI：
10.1007/s11427-021-2067-7
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发表时间：
2022-04-01
影响因子：
9.1
通讯作者：
Cai, Xiujun
中科院分区：
文献类型：
--
作者：
Chen, Jiang;Jiang, Shi;Cai, Xiujun
The treatment of hepatocellular carcinoma (HCC) has been dominated by multikinase inhibitors for more than a decade. However, drug resistance can severely restrict the efficacy of these drugs. Using CRISPR/CAS9 genome library screening, we evaluated Kelch-like ECH-associated protein 1 (KEAP1) as a key regulator of sorafenib’s susceptibility in HCC. We also investigated whether KEAP1’s knockdown can stabilize nuclear factor (erythroid-derived 2)-like 2 (NRF2) protein levels that led to sorafenib’s resistance, including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growthin vitroandin vivo. Furthermore, we clarified that fibroblast growth factor 21 (FGF21) is an important downstream regulator of NRF2 in HCC. Intriguingly, we observed that FGF21 bound to NRF2 through the C-terminus of FGF21, thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC. These findings, therefore, propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.
