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.

中文翻译：

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N6-甲基腺苷修饰激活丝氨酸合成途径以介导肝癌的治疗耐药性


代谢适应是癌症生长的重要驱动力，对癌症治疗构成重大障碍。在此，我们揭示了 m6A 介导的丝氨酸合成途径 （SSP） 调节在肝细胞癌 （HCC） 发展和治疗耐药中的作用。我们证明，高度特异性 m6A 抑制剂 （STM2457） 的治疗有效抑制了肝脏特异性 Tp53 敲除和 Myc 过表达驱动的小鼠的 HCC 细胞系生长并抑制了自发性 HCC 形成。使用 GLORI-seq，我们在人 HCC 细胞系中描绘了单碱基分辨率的 m6A 景观。有趣的是，我们在 SSP 中确定了三种核心酶 （PHGDH、PSAT1 和 PSPH） 作为 METTL3 介导的 m6A 修饰的新靶点。在这些 SSP 基因中，m6A 修饰招募了 m6A 读取IGF2BP3来稳定它们的 mRNA 转录本，从而增强它们在 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，以促进蛋白质表达和抗氧化剂的产生。STM2457 治疗减弱了丝氨酸合成途径，诱导了氧化应激，并使 HCC 细胞对索拉非尼和乐伐替尼治疗敏感。总之，我们的研究结果表明，靶向 m6A 可能是 HCC 治疗的潜在治疗策略。