AMPK-dependent phosphorylation of HDAC8 triggers PGM1 expression to promote lung cancer cell survival under glucose starvation
AMPK-dependent phosphorylation of HDAC8 triggers PGM1 expression to promote lung cancer cell survival under glucose starvation
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HDAC8 的 AMPK 依赖性磷酸化触发 PGM1 表达，促进肺癌细胞在葡萄糖饥饿下存活
DOI：
10.1016/j.canlet.2020.03.007
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发表时间：
2020-05-28
期刊：
影响因子：
9.7
通讯作者：
Shan, Changliang
中科院分区：
文献类型：
--
作者：
Li, Yanping;Liang, Ronghui;Shan, Changliang
癌细胞经历代谢重编程以在增加的能量需求的环境下维持自身的存活;然而，癌细胞确保在葡萄糖剥夺应激条件下存活的机制仍然难以捉摸。在这里，我们表明，剥夺葡萄糖，显着激活糖原途径，伴随着升高的磷酸葡萄糖变位酶1（PGM 1）的表达。我们进一步确定，AMP激活的蛋白激酶（AMPK）刺激PGM 1的表达诱导组蛋白去乙酰化酶8（HDAC 8）磷酸化。此外，我们证明了葡萄糖剥夺诱导的AMPK激活刺激HDAC 8从细胞核易位到细胞质，从而破坏HDAC 8和组蛋白3之间的结合。PGM 1的表达也被发现对肺癌糖酵解、氧化戊糖磷酸途径和葡萄糖剥夺条件下的氧化磷酸化至关重要，并进一步导致参与ERK 1/2介导的葡萄糖代谢的代谢酶的异常表达。最后，发现PGM 1在患者的肺癌组织中高表达，这与预后不良相关。综上所述，这些结果表明，通过葡萄糖剥夺激活AMPK导致PGM 1表达增强，这是代谢开关的重要组成部分，以促进癌症进展，表明PGM 1是有希望的抗癌治疗靶点。
Cancer cells undergo metabolic reprogramming to sustain their own survival under an environment of increased energy demand; however, the mechanism by which cancer cells ensure survival under glucose deprivation stressed conditions remains elusive. Here, we show that deprivation of glucose, dramatically activated the glycogen pathway, accompanied by elevated phosphoglucomutase 1 (PGM1) expression. We further identified that AMP-activated protein kinase (AMPK) stimulated PGM1 expression by inducing histone deacetylase 8 (HDAC8) phosphorylation. Moreover, we demonstrated that glucose deprivation-induced AMPK activation stimulated the translocation of HDAC8 from the nucleus to the cytoplasm, consequently disrupting the binding between HDAC8 and histone 3. PGM1 expression was also found to be critical for lung cancer glycolysis, the oxidative pentose phosphate pathway, and oxidative phosphorylation under glucose deprivation conditions, and further led to the aberrant expression of metabolic enzymes involved in glucose metabolism mediated by ERK1/2. Finally, PGM1 was found to be highly expressed in lung cancer tissues from patients, which correlated with a poor prognosis. Taken together, these results revealed that AMPK activation by glucose deprivation leads to enhanced PGM1 expression, an essential component of the metabolic switch, to facilitate cancer progression, suggesting PGM1 as promising anti-cancer treatment targets.