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首页> 外文期刊>Cell cycle >Centromere protein F (CENPF), a microtubule binding protein, modulates cancer metabolism by regulating pyruvate kinase M2 phosphorylation signaling
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Centromere protein F (CENPF), a microtubule binding protein, modulates cancer metabolism by regulating pyruvate kinase M2 phosphorylation signaling

机译:Centromere蛋白F(CENPF),微管结合蛋白,通过调节丙酮酸激酶M2磷酸化信号传导来调节癌症代谢

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Prostate cancer (PC) is the most commonly diagnosed cancer in men and is the second leading cause of male cancer-related death in North America. Metabolic adaptations in malignant PC cells play a key role in fueling the growth and progression of the disease. Unfortunately, little is known regarding these changes in cellular metabolism. Here, we demonstrate that centromere protein F (CENPF), a protein associated with the centromere-kinetochore complex and chromosomal segregation during mitosis, is mechanically linked to altered metabolism and progression in PC. Using the CRISPR-Cas9 system, we silenced the gene for CENPF in human PC3 cells. These cells were found to have reduced levels of epithelial-mesenchymal transition markers and inhibited cell proliferation, migration, and invasion. Silencing of CENPF also simultaneously improved sensitivity to anoikis-induced apoptosis. Mass spectrometry analysis of tyrosine phosphorylated proteins from CENPF knockout (CENPFKO) and control cells revealed that CENPF silencing increasedinactive forms of pyruvate kinase M2, a rate limiting enzyme needed for an irreversible reaction in glycolysis. Furthermore, CENPFKO cells had reduced global bio-energetic capacity, acetyl-CoA production, histone acetylation, and lipid metabolism, suggesting that CENPF is a critical regulatorof cancer metabolism, potentially through its effects on mitochondrial functioning. Additionalquantitative immunohistochemistry and imaging analyzes on a series of PC tumor microarraysdemonstrated that CENPF expression is significantly increased in higher-risk PC patients. Based on these findings, we suggest the CENPF may be an important regulator of PC metabolism through its role in the mitochondria.
机译:前列腺癌(PC)是男性最常见的癌症,是北美男性癌症相关死亡的第二个主要原因。恶性PC细胞的代谢适应在促进疾病的生长和进展方面发挥着关键作用。不幸的是,关于细胞新陈代谢的这些变化很少。这里,我们证明了Centromere蛋白F(CENPF),与Centromere-Kinetochore复合物和染色体分离期间的染色体偏析相关的蛋白质,与PC中的改变的代谢和进展机械相关。使用CRISPR-CAS9系统,我们在人PC3细胞中沉默于CENPF的基因。发现这些细胞具有降低的上皮 - 间充质过渡标志物水平,并抑制细胞增殖,迁移和侵袭。 CENPF的沉默也同时提高了对Anoikis诱导的细胞凋亡的敏感性。来自CENPF敲除(CENPFKO)和对照细胞的酪氨酸磷酸化蛋白质的质谱分析显示,CENPF沉默的丙酮酸激酶M2的型丙酮酸激酶M2,在糖醇分解中不可逆反应所需的速率限制酶。此外,CENPFKO细胞具有降低全球生物能量容量,乙酰基 - COA生产,组蛋白乙酰化和脂质代谢,表明CENPF是癌症代谢的临界调节剂,可能通过其对线粒体功能的影响。在一系列PC肿瘤微阵列癫痫发作的辅助免疫组织化学和成像分析中,CENPF表达在高风险的PC患者中显着增加。基于这些发现,我们建议CENPF通过其在线粒体中的作用,CENPF可能是PC代谢的重要调节因素。

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