南京大学王宏伟等研究人员合作发现，破坏的蛋氨酸循环通过表观遗传，调控REDD1引发癌症恶病质中的肌肉萎缩。相关论文于2024年12月26日发表在《细胞—代谢》杂志上。

研究人员报告了在癌症恶病质过程中，骨骼肌中的蛋氨酸循环被破坏，导致内质网应激和DNA低甲基化，引发DNA损伤诱导转录本4（Ddit4）基因的表达。该基因编码发育调控与DNA损伤反应1（REDD1）蛋白。

通过去除或药理学抑制DNA甲基转移酶3A（DNMT3A），来靶向DNA甲基化会加重恶病质，而恢复DNMT3A表达或敲除REDD1，则能缓解小鼠癌症恶病质引起的骨骼肌萎缩。蛋氨酸补充能够以DNMT3A依赖的方式恢复Ddit4启动子的DNA甲基化，从而抑制激活转录因子4（ATF4）介导的Ddit4转录。

因此，通过确定蛋氨酸/S-腺苷甲硫氨酸（SAM）-DNMT3A-DNA低甲基化-Ddit4/REDD1轴，该研究为癌症恶病质的表观遗传机制提供了分子洞察，并建议营养补充作为预防或逆转恶病质性肌肉萎缩的有前景的治疗策略。

据介绍，必需氨基酸蛋氨酸在一碳代谢中发挥关键作用，促进SAM的生成，SAM是DNA甲基化的关键供体，进而调节基因表达。

附：英文原文

Title: Disrupted methionine cycle triggers muscle atrophy in cancer cachexia through epigenetic regulation of REDD1

Author: Kai Lin, Lulu Wei, Ranran Wang, Li Li, Shiyu Song, Fei Wang, Meiwei He, Wenyuan Pu, Jinglin Wang, Junaid Wazir, Wangsen Cao, Xiaozhong Yang, Eckardt Treuter, Rongrong Fan, Yongxiang Wang, Zhiqiang Huang, Hongwei Wang

Issue&Volume: 2024-12-26

Abstract: The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAM), a critical supplier for DNA methylation and thereby a modulator of gene expression. Here, we report that the methionine cycle is disrupted in skeletal muscle during cancer cachexia, leading to endoplasmic reticulum stress and DNA hypomethylation-induced expression of the DNA damage inducible transcript 4 (Ddit4) gene, encoding the regulated in development and DNA damage response 1 (REDD1) protein. Targeting DNA methylation by depletion or pharmacological inhibition of DNA methyltransferase 3A (DNMT3A) exacerbates cachexia, while restoring DNMT3A expression or REDD1 knockout alleviates cancer cachexia-induced skeletal muscle atrophy in mice. Methionine supplementation restores DNA methylation of the Ddit4 promoter in a DNMT3A-dependent manner, thereby inhibiting activating transcription factor 4 (ATF4)-mediated Ddit4 transcription. Thus, with the identification of the methionine/SAM-DNMT3A/DNA hypomethylation-Ddit4/REDD1 axis, our study provides molecular insights into an epigenetic mechanism underlying cancer cachexia, and it suggests nutrient supplementation as a promising therapeutic strategy to prevent or reverse cachectic muscle atrophy.

DOI: 10.1016/j.cmet.2024.10.017

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00413-3