4-羟苯基丙酮酸双加氧酶通过LKB1-AMPK / HDAC10 / G6PD轴介导的戊糖磷酸途径（PPP）通量促进肺癌的生长。,Cell Death & Disease

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4-羟苯基丙酮酸双加氧酶通过LKB1-AMPK / HDAC10 / G6PD轴介导的戊糖磷酸途径（PPP）通量促进肺癌的生长。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-07-08 , DOI: 10.1038/s41419-019-1756-1
Changliang Shan _{1,

2} , Zhaoliang Lu ₃ , Zhen Li ₂ , Hao Sheng ₂ , Jun Fan ₄ , Qi Qi ₅ , Shuangping Liu ₆ , Shuai Zhang ₇

Affiliation

4-羟苯基丙酮酸双加氧酶（HPD）是酪氨酸代谢的重要调节剂。但是，HPD对癌症代谢和肿瘤发生的确切作用尚不清楚。在这项研究中，我们发现HPD在肺癌中高表达，其高表达与肺癌患者的不良预后相关。抑制的HPD表达足以降低氧化性戊糖磷酸途径（PPP）流量，从而导致RNA生物合成减少和活性氧（ROS）水平升高，癌细胞增殖减弱和肿瘤生长。从机理上讲，HPD不仅会促进酪氨酸分解代谢，从而导致乙酰辅酶A水平升高，而乙酰辅酶A水平是组蛋白乙酰化的来源，而且还能刺激组蛋白脱乙酰基酶10（HDAC10）从细胞核向肿瘤抑制肝激酶B1（LKB1）-AMP激活的蛋白激酶（AMPK）信号传导介导的转运。两者都控制着组蛋白的乙酰化修饰，从而增强了重要的PPP酶葡萄糖6磷酸脱氢酶（G6PD）的转录。因此，这项研究揭示了HPD作为LKB1-AMPK信号介导的HDAC10核位置的新型调节剂，它有助于G6PD表达促进肿瘤生长，这是肺癌治疗的有希望的靶标。

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4-hydroxyphenylpyruvate dioxygenase promotes lung cancer growth via pentose phosphate pathway (PPP) flux mediated by LKB1-AMPK/HDAC10/G6PD axis.

4-hydroxyphenylpyruvate dioxygenase (HPD) is an important modifier of tyrosine metabolism. However, the precise contribution of HPD to cancer metabolism and tumorigenesis remains unclear. In this study, we found that HPD was highly expressed in lung cancer and its higher expression correlated with poor prognosis in lung cancer patients. Suppressed HPD expression was sufficient to decrease oxidative pentose phosphate pathway (PPP) flux, leading to reduced RNA biosynthesis and enhanced reactive oxygen species (ROS) level, attenuated cancer cell proliferation, and tumor growth. Mechanistically, HPD not only promotes tyrosine catabolism leading to increased acetyl-CoA levels, the source of histone acetylation, but also stimulates histone deacetylase 10 (HDAC10) translocation from the nucleus into the cytoplasm mediated by tumor suppressor liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) signaling. Both controlled histone acetylation modification, which enhanced transcription of the important PPP enzyme Glucose-6-Phosphate Dehydrogenase (G6PD). Thus, this study reveals HPD as a novel regulator of LKB1-AMPK signaling-mediated HDAC10 nuclear location, which contributes to G6PD expression in promoting tumor growth, which is a promising target for lung cancer treatment.

更新日期：2019-07-08

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