代谢调节剂 PDHK1 在 PTEN 缺陷细胞和癌症中的合成必要性。
Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers.
机构信息
Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
出版信息
Cell Rep. 2019 Aug 27;28(9):2317-2330.e8. doi: 10.1016/j.celrep.2019.07.063.
Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.
摘要
磷酸酶和张力蛋白同源物缺失于第 10 号染色体（PTEN）是一种肿瘤抑制因子和双功能脂质及蛋白磷酸酶。我们报告称，代谢调节剂丙酮酸脱氢酶激酶 1（PDHK1）是 PTEN 缺失型癌症和正常细胞中的合成必需基因。PTEN 蛋白磷酸酶使核因子 κB（NF-κB）激活蛋白（NKAP）去磷酸化，从而限制 NFκB 的激活，以抑制 PDHK1 的表达，PDHK1 是 NF-κB 的靶基因。PTEN 蛋白磷酸酶的缺失会上调 PDHK1，从而诱导有氧糖酵解和 PDHK1 细胞依赖性。PTEN 缺失的人类肿瘤中 PDHK1 增加，这是患者生存率降低的生物标志物。本研究揭示了一个受 PTEN 调控的信号通路，并发现 PDHK1 是 PTEN 缺失型癌症的一个潜在靶点。
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