Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine
Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine
复制标题
Cul4A-DDB1介导的磷酸甘油酸脱氢酶单泛素化通过增加S-腺苷甲硫氨酸促进结直肠癌转移
DOI：
10.1172/jci146187
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发表时间：
2021-11-01
影响因子：
15.9
通讯作者：
Yang, Weiwei
中科院分区：
文献类型：
--
作者：
Zhang, Yajuan;Yu, Hua;Yang, Weiwei
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的迁移仍然知之甚少。磷酸甘油酸脱氢酶(PHGDH)催化3-磷酸甘油酸氧化为3-磷酸氧基丙酮酸，这是丝氨酸生物合成的第一步。在这里，我们发现在结直肠癌细胞中，PHGDH146位的基于cullin 4A的E3连接酶复合体是单核苷酸的，它通过招募伴侣蛋白DNAJ同源A家族成员1来促进其四聚体的形成，从而增加丝氨酸、甘氨酸和S腺苷蛋氨酸的水平，从而增强PHGDHs的活性。SAM水平的增加通过启动包含1A的SET结构域介导的组蛋白H3K4的三甲基化，上调细胞黏附基因(层粘连蛋白亚单位伽马2和富含半胱氨酸的血管生成诱导剂61)的表达，从而促进肿瘤细胞的迁移和结直肠癌转移。有趣的是，肿瘤或血液样本中的SAM水平与结直肠癌患者的转移复发相关。我们的发现不仅揭示了SAM促进肿瘤转移的潜在新的作用和机制，而且还揭示了一种通过单素化来调节PHGDH活性的机制。
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.