Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers
Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers
复制标题
代谢调节因子PDHK1在PTEN缺失细胞及癌症中的合成致死性
DOI：
10.1016/j.celrep.2019.07.063
复制
发表时间：
2019-08-27
期刊：
影响因子：
8.8
通讯作者：
Bivona, Trever G.
中科院分区：
文献类型：
--
作者：
Chatterjee, Nilanjana;Pazarentzos, Evangelos;Bivona, Trever G.
10号染色体上缺失的磷酸酶和紧张素同源物（PTEN）是一种肿瘤抑制酶和双功能脂质和蛋白磷酸酶。我们报道代谢调节因子丙酮酸脱氢酶激酶（PDHK1）是pten缺陷癌细胞和正常细胞的合成必需基因。PTEN蛋白磷酸酶可使核因子κ B （NF- κ B）激活蛋白（NKAP）去磷酸化，并限制NF κ B的激活，从而抑制NF- κ B靶基因PDHK1的表达。PTEN蛋白磷酸酶的缺失可上调PDHK1，诱导有氧糖酵解和PDHK1细胞依赖性。pten缺陷的人类肿瘤中PDHK1升高，PDHK1是患者生存率降低的生物标志物。本研究揭示了pten调控的信号通路，并揭示PDHK1是pten缺陷癌症的潜在靶点。
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 kinasel (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor kappa B (NF-kappa B)-activating protein (NKAP) and limits NF kappa B activation to suppress expression of PDHK1, a NF-kappa B 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.