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缺氧诱导的 PGK1 琥珀酰化下调通过协调糖酵解和三羧酸循环促进肿瘤发生。

Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.

机构信息

Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.

出版信息

Nat Commun. 2024 Aug 12;15(1):6915. doi: 10.1038/s41467-024-51232-w.

DOI:10.1038/s41467-024-51232-w
PMID:39134530
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11319824/
Abstract

Protein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer.

摘要

蛋白质翻译后修饰（PTMs）对于癌细胞适应缺氧至关重要；然而，赖氨酸巴豆酰化（Kcr）在缺氧中的功能意义尚不清楚。在此，我们报告了在常氧和缺氧条件下的全局巴豆酰组蛋白组学的定量蛋白质组学分析，并在 MDA-MB231 细胞中鉴定了 101 个蛋白质中的 128 个 Kcr 位点变化。具体而言，我们观察到在缺氧条件下磷酸甘油酸激酶 1（PGK1）的 K131cr、K156cr 和 K220cr 显著减少。烯酰辅酶 A 水合酶 1（ECHS1）上调并与 PGK1 相互作用，导致 PGK1 Kcr 在缺氧下下调。PGK1 Kcr 的消除通过激活丙酮酸脱氢酶激酶 1（PDHK1）促进糖酵解并抑制线粒体丙酮酸代谢。PGK1 K131cr 水平低与乳腺癌的恶性程度和预后不良相关。我们的研究结果表明，PGK1 Kcr 是协调糖酵解和三羧酸（TCA）循环的信号，可作为乳腺癌的诊断指标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0629/11319824/114f41dff5f1/41467_2024_51232_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0629/11319824/114f41dff5f1/41467_2024_51232_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0629/11319824/6a700ee5eac3/41467_2024_51232_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0629/11319824/8732ed3b92e6/41467_2024_51232_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0629/11319824/0e2a3588ecb4/41467_2024_51232_Fig3_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0629/11319824/67df2d05819c/41467_2024_51232_Fig5_HTML.jpg
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