N6-Methyladenosine modification activates the serine synthesis pathway to mediate therapeutic resistance in liver cancer.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-26 DOI:10.1016/j.ymthe.2024.10.025
For-Fan Chan, Kenneth Kin-Leung Kwan, Do-Hyun Seoung, Don Wai-Ching Chin, Irene Oi-Lin Ng, Carmen Chak-Lui Wong, Chun-Ming Wong
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引用次数: 0

Abstract

Metabolic adaptation serves as a significant driving force for cancer growth and poses a substantial obstacle for cancer therapies. Herein, we unraveled the role of m6A-mediated serine synthesis pathway (SSP) regulation in both hepatocellular carcinoma (HCC) development and therapeutic resistance. We demonstrated that treatment of highly specific m6A inhibitor (STM2457) effectively inhibited HCC cell line growth and suppressed spontaneous HCC formation in mice driven by liver-specific Tp53 knockout and Myc overexpression. Using GLORI-seq, we delineated a single-base-resolution m6A landscape in human HCC cell lines. Interestingly, we identified three core enzymes in the SSP (PHGDH, PSAT1, and PSPH) as novel targets of METTL3-mediated m6A modification. In these SSP genes, m6A modification recruited m6A reader IGF2BP3 to stabilize their mRNA transcripts, thereby enhancing their mRNA and protein expression in HCC cells. Most importantly, our GLORI-seq data revealed that sorafenib-resistant HCC cells elevated m6A modification in SSP genes to promote protein expression and antioxidant production. STM2457 treatment attenuated the serine synthesis pathway, induced oxidative stress, and sensitized HCC cells to sorafenib and lenvatinib treatments. In conclusion, our findings suggest that targeting m6A could be a potential therapeutic strategy for HCC treatment.

N6-甲基腺苷(m6A)修饰激活丝氨酸合成途径,介导肝癌的耐药性。
代谢适应是癌症生长的重要驱动力,也是癌症疗法的一大障碍。在本文中,我们揭示了 m6A 介导的丝氨酸合成通路调控在肝细胞癌(HCC)发展和耐药性中的作用。我们证明,高度特异性的 m6A 抑制剂(STM2457)能有效抑制 HCC 细胞系的生长,并抑制肝脏特异性 Tp53 基因敲除和 Myc 过表达驱动的小鼠自发性 HCC 的形成。利用 GLORI-seq 技术,我们在人类 HCC 细胞系中绘制了单碱基分辨率的 m6A 图谱。有趣的是,我们发现丝氨酸合成途径中的三个核心酶(PHGDH、PSAT1 和 PSPH)是 METTL3 介导的 m6A 修饰的新靶标。在这些 SSP 基因中,m6A 修饰招募了 IGF2BP3 阅读器来稳定它们的 mRNA 转录本,从而提高了它们在 HCC 细胞中的 mRNA 和蛋白质表达。最重要的是,我们的GLORI-seq数据显示,索拉非尼耐药的HCC细胞提高了SSP基因中的m6A修饰,从而促进了蛋白质的表达和抗氧化剂的产生。STM2457治疗可减轻丝氨酸合成途径,诱导氧化应激,并使HCC细胞对索拉非尼和伦伐替尼治疗敏感。总之,我们的研究结果表明,靶向m6A可能是治疗HCC的一种潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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