PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma.
PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma.
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DOI：
10.1038/s41467-023-36708-5
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发表时间：
2023-02-23
影响因子：
16.6
通讯作者：
Huang, Canhua
中科院分区：
文献类型：
--
作者：
Wang, Kui;Luo, Li;Fu, Shuyue;Wang, Mao;Wang, Zihao;Dong, Lixia;Wu, Xingyun;Dai, Lunzhi;Peng, Yong;Shen, Guobo;Chen, Hai-Ning;Nice, Edouard Collins;Wei, Xiawei;Huang, Canhua
丝氨酸的合成对肿瘤的生长和存活至关重要，但其在肿瘤中的调控机制尚不清楚。在这里，使用综合代谢组学和转录组学分析，我们显示了代谢物和转录谱之间的异质性。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第一限速酶磷酸甘油酸脱氢酶（PHGDH）的表达明显下调。有趣的是，由于蛋白精氨酸甲基转移酶1 （PRMT1）介导PHGDH在精氨酸236位点的甲基化，从而增强了PHGDH的催化活性，从而增加了丝氨酸水平。prmt1介导的PHGDH甲基化和激活增强了丝氨酸合成，改善了氧化应激，促进了体外和体内肝癌的生长。此外，prmt1介导的PHGDH甲基化与人HCC组织中PHGDH超激活和丝氨酸积累相关，可预测HCC患者预后不良。值得注意的是，在肝癌患者来源的异种移植（PDX）模型和皮下肝癌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甲基化可抑制丝氨酸合成并抑制HCC生长。总之，我们的研究结果揭示了PHGDH活性和丝氨酸合成的调控机制，并提示PHGDH甲基化是HCC的潜在治疗脆弱性。在肝细胞癌（HCC）中，蛋白精氨酸甲基化在癌细胞丝氨酸代谢中的作用仍有待探讨。在这里，作者表明磷酸甘油酸脱氢酶（PHGDH）被prmt1介导的R236甲基化激活，促进丝氨酸合成、氧化还原稳态和HCC生长。
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. The role of protein arginine methylation in serine metabolism of cancer cells in hepatocellular carcinoma (HCC) remains to be explored. Here, the authors show that phosphoglycerate dehydrogenase (PHGDH) is activated by PRMT1-mediated R236 methylation, promoting serine synthesis, redox homeostasis and HCC growth.
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DOI：
10.1002/hep.29561
发表时间：
2018-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Luo P;Yin P;Hua R;Tan Y;Li Z;Qiu G;Yin Z;Xie X;Wang X;Chen W;Zhou L;Wang X;Li Y;Chen H;Gao L;Lu X;Wu T;Wang H;Niu J;Xu G
通讯作者：
Xu G
通过化学蛋白质组学和表型分析鉴定新型 PHGDH 共价抑制剂
DOI：
10.1016/j.apsb.2021.06.008
发表时间：
2022-01
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Chen C;Zhu T;Liu X;Zhu D;Zhang Y;Wu S;Han C;Zhang H;Luo J;Kong L
通讯作者：
Kong L
SWATH-MS 定量蛋白质组学揭示肝细胞癌组织中复杂的代谢重编程
影响因子：
4.6
作者：
Gao Y;Wang X;Sang Z;Li Z;Liu F;Mao J;Yan D;Zhao Y;Wang H;Li P;Ying X;Zhang X;He K;Wang H
通讯作者：
Wang H
影响因子：
5.3
作者：
Balint, BL;Szanto, A;Nagy, L
通讯作者：
Nagy, L
影响因子：
15.9
作者：
Liu, Juan;Zhang, Cen;Feng, Zhaohui
通讯作者：
Feng, Zhaohui