丝氨酸合成对肿瘤生长和存活至关重要,但其在癌症中的调节机制仍不清楚。在这里,我们使用综合代谢组学和转录组学分析,展示了代谢物和转录物谱之间的异质性。具体而言,肝细胞癌(HCC)组织中丝氨酸水平升高,而丝氨酸生物合成途径中的第一个限速酶磷酸甘油酸脱氢酶(PHGDH)的表达显着下调。有趣的是,由于蛋白精氨酸甲基转移酶 1 (PRMT1) 介导的 PHGDH 在精氨酸 236 的甲基化,丝氨酸水平的增加是通过增强 PHGDH 催化活性获得的。PRMT1 介导的 PHGDH 甲基化和激活增强丝氨酸合成,改善氧化应激,并促进 HCC 生长体外和体内。此外,PRMT1 介导的 PHGDH 甲基化与人类 HCC 组织中的 PHGDH 过度活化和丝氨酸积累相关,并且可预测 HCC 患者的不良预后。值得注意的是,在 HCC 患者来源的异种移植 (PDX) 模型和皮下 HCC 细胞来源的异种移植模型中,用 TAT 标记的非甲基化肽阻断 PHGDH 甲基化会抑制丝氨酸合成并抑制 HCC 的生长。总体而言,我们的研究结果揭示了 PHGDH 活性和丝氨酸合成的调节机制,并表明 PHGDH 甲基化是 HCC 中潜在的治疗弱点。用 TAT 标记的非甲基化肽阻断 PHGDH 甲基化可抑制丝氨酸合成并抑制 HCC 患者来源的异种移植 (PDX) 模型和皮下 HCC 细胞来源的异种移植模型中的 HCC 生长。总体而言,我们的研究结果揭示了 PHGDH 活性和丝氨酸合成的调节机制,并表明 PHGDH 甲基化是 HCC 中潜在的治疗弱点。用 TAT 标记的非甲基化肽阻断 PHGDH 甲基化可抑制丝氨酸合成并抑制 HCC 患者来源的异种移植 (PDX) 模型和皮下 HCC 细胞来源的异种移植模型中的 HCC 生长。总体而言,我们的研究结果揭示了 PHGDH 活性和丝氨酸合成的调节机制,并表明 PHGDH 甲基化是 HCC 中潜在的治疗弱点。
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PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma
Serine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Here, using integrative metabolomics and transcriptomics analyses, we show a heterogeneity between metabolite and transcript profiles. Specifically, the level of serine in hepatocellular carcinoma (HCC) tissues is increased, whereas the expression of phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in serine biosynthesis pathway, is markedly downregulated. Interestingly, the increased serine level is obtained by enhanced PHGDH catalytic activity due to protein arginine methyltransferase 1 (PRMT1)-mediated methylation of PHGDH at arginine 236. PRMT1-mediated PHGDH methylation and activation potentiates serine synthesis, ameliorates oxidative stress, and promotes HCC growth in vitro and in vivo. Furthermore, PRMT1-mediated PHGDH methylation correlates with PHGDH hyperactivation and serine accumulation in human HCC tissues, and is predictive of poor prognosis of HCC patients. Notably, blocking PHGDH methylation with a TAT-tagged nonmethylated peptide inhibits serine synthesis and restrains HCC growth in an HCC patient-derived xenograft (PDX) model and subcutaneous HCC cell-derived xenograft model. Overall, our findings reveal a regulatory mechanism of PHGDH activity and serine synthesis, and suggest PHGDH methylation as a potential therapeutic vulnerability in HCC.