State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China.
J Clin Invest. 2021 Nov 1;131(21). doi: 10.1172/JCI146187.
Although serine metabolism plays a crucial role in the proliferation and survival of tumor cells, how it supports tumor cell migration remains poorly understood. Phosphoglycerate dehydrogenase (PHGDH) catalyzes the oxidation of 3-phosphoglycerate to 3-phosphonooxypyruvate, the first committed step in de novo serine biosynthesis. Here we show that PHGDH was monoubiquitinated by cullin 4A-based E3 ligase complex at lysine 146 in colorectal cancer (CRC) cells, which enhanced PHGDH activity by recruiting a chaperone protein, DnaJ homolog subfamily A member 1, to promote its tetrameric formation, thereby increasing the levels of serine, glycine, and S-adenosylmethionine (SAM). Increased levels of SAM upregulated the expression of cell adhesion genes (laminin subunit gamma 2 and cysteine rich angiogenic inducer 61) by initiating SET domain containing 1A-mediated trimethylation of histone H3K4, thereby promoting tumor cell migration and CRC metastasis. Intriguingly, SAM levels in tumors or blood samples correlated with the metastatic recurrence of patients with CRC. Our finding not only reveals a potentially new role and mechanism of SAM-promoted tumor metastasis but also demonstrates a regulatory mechanism of PHGDH activity by monoubiquitination.
尽管丝氨酸代谢在肿瘤细胞的增殖和存活中起着至关重要的作用，但它如何支持肿瘤细胞迁移仍知之甚少。磷酸甘油酸脱氢酶（PHGDH）催化 3-磷酸甘油酸氧化为 3-磷酸烯醇丙酮酸，这是从头合成丝氨酸的第一步。在这里，我们表明 PHGDH 在结直肠癌（CRC）细胞中被基于 cullin 4A 的 E3 连接酶复合物在赖氨酸 146 处单泛素化，通过招募伴侣蛋白 DnaJ 同源物亚家族 A 成员 1 来增强 PHGDH 活性，从而促进其四聚体形成，从而增加丝氨酸、甘氨酸和 S-腺苷甲硫氨酸（SAM）的水平。SAM 水平的增加通过起始 SET 结构域包含蛋白 1A 介导的组蛋白 H3K4 的三甲基化，上调细胞黏附基因（层粘连蛋白亚单位γ 2 和富含半胱氨酸的血管生成诱导因子 61）的表达，从而促进肿瘤细胞迁移和 CRC 转移。有趣的是，肿瘤或血液样本中的 SAM 水平与 CRC 患者的转移性复发相关。我们的发现不仅揭示了 SAM 促进肿瘤转移的一个潜在的新作用和机制，而且还证明了 PHGDH 活性通过单泛素化的调节机制。
