奥沙利铂
肝细胞癌
磷酸戊糖途径
癌症研究
化学
医学
内科学
生物化学
新陈代谢
癌症
糖酵解
结直肠癌
作者
Xiaohan Jin,Yong-rui Lv,Fengjie Bie,Jin‐Ling Duan,Chao Ma,Miaomiao Dai,Jiewei Chen,Lianghe Lu,Shui-Dan Xu,Jie Zhou,Si Li,Jiong Bi,Fengwei Wang,Dan Xie,Muyan Cai
标识
DOI:10.1038/s41418-024-01406-2
摘要
Abstract Oxaliplatin-based therapeutics is a widely used treatment approach for hepatocellular carcinoma (HCC) patients; however, drug resistance poses a significant clinical challenge. Epigenetic modifications have been implicated in the development of drug resistance. In our study, employing siRNA library screening, we identified that silencing the m 6 A writer METTL3 significantly enhanced the sensitivity to oxaliplatin in both in vivo and in vitro HCC models. Further investigations through combined RNA-seq and non-targeted metabolomics analysis revealed that silencing METTL3 impeded the pentose phosphate pathway (PPP), leading to a reduction in NADPH and nucleotide precursors. This disruption induced DNA damage, decreased DNA synthesis, and ultimately resulted in cell cycle arrest. Mechanistically, METTL3 was found to modify E3 ligase TRIM21 near the 3’UTR with N 6 -methyladenosine, leading to reduced RNA stability upon recognition by YTHDF2. TRIM21, in turn, facilitated the degradation of the rate-limiting enzyme of PPP, G6PD, through the ubiquitination-proteasome pathway. Importantly, high expression of METTL3 was significantly associated with adverse prognosis and oxaliplatin resistance in HCC patients. Notably, treatment with the specific METTL3 inhibitor, STM2457, significantly improved the efficacy of oxaliplatin. These findings underscore the critical role of the METTL3/TRIM21/G6PD axis in driving oxaliplatin resistance and present a promising strategy to overcome chemoresistance in HCC.
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