Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Shan C

PROVIDER: S-EPMC6614486 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Shan Changliang C Lu Zhaoliang Z Li Zhen Z Sheng Hao H Fan Jun J Qi Qi Q Liu Shuangping S Zhang Shuai S

Cell death & disease 20190708 7

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 ox ...[more]

PMID: 31285420

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Project description:Bacillus megaterium is a bacterium of great importance as a plant-beneficial bacterium in agricultural applications and in industrial bioproduction of proteins. Understanding intracellular processing of carbohydrates in this species is crucial to predicting natural carbon utilization as well as informing strategies in metabolic engineering. Here, we applied stable isotope-assisted metabolomics profiling and metabolic flux analysis to elucidate, at high resolution, the connections of the different catabolic routes for carbohydrate metabolism immediately following substrate uptake in B. megaterium QM B1551. We performed multiple 13C tracer experiments to obtain both kinetic and long-term 13C profiling of intracellular metabolites. In addition to the direct phosphorylation of glucose to glucose-6-phosphate (G6P) prior to oxidation to 6-phosphogluconate (6P-gluconate), the labeling data also captured glucose catabolism through the gluconate pathway involving glucose oxidation to gluconate followed by phosphorylation to 6P-gluconate. Our data further confirmed the absence of the Entner-Doudoroff pathway in B. megaterium and showed that subsequent catabolism of 6P-gluconate was instead through the oxidative pentose-phosphate (PP) pathway. Quantitative flux analysis of glucose-grown cells showed equal partition of consumed glucose from G6P to the Embden-Meyerhof-Parnas (EMP) pathway and from G6P to the PP pathway through 6P-gluconate. Growth on fructose alone or xylose alone was consistent with the ability of B. megaterium to use each substrate as a sole source of carbon. However, a detailed 13C mapping during simultaneous feeding of B. megaterium on glucose, fructose, and xylose indicated non-uniform intracellular investment of the different carbohydrate substrates. Flux of glucose-derived carbons dominated the gluconate pathway and the PP pathway, whereas carbon flux from both glucose and fructose populated the EMP pathway; there was no assimilatory flux of xylose-derived carbons. Collectively, our findings provide new quantitative insights on the contribution of the different catabolic routes involved in initiating carbohydrate catabolism in B. megaterium and related Bacillus species.

Dataset Information

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

Publications

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

Similar Datasets

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