2. Academic Validation
  3. 4-hydroxyphenylpyruvate dioxygenase promotes lung cancer growth via pentose phosphate pathway (PPP) flux mediated by LKB1-AMPK/HDAC10/G6PD axis

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

  • Cell Death Dis. 2019 Jul 8;10(7):525. doi: 10.1038/s41419-019-1756-1.
Changliang Shan 1 2,  Zhaoliang Lu 3,  Zhen Li 4,  Hao Sheng 4,  Jun Fan 5,  Qi Qi 6,  Shuangping Liu 7,  Shuai Zhang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, 300350, Tianjin, China. changliangshan@nankai.edu.cn.
  • 2 The First Affiliated Hospital, Biomedical Translational Research Institute, Jinan University, 510632, Guangzhou, Guangdong, China. changliangshan@nankai.edu.cn.
  • 3 Department of Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, Guangdong, China.
  • 4 The First Affiliated Hospital, Biomedical Translational Research Institute, Jinan University, 510632, Guangzhou, Guangdong, China.
  • 5 Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, 510632, Guangzhou, Guangdong, China.
  • 6 Department of Pharmacology, School of Medicine, Jinan University, 510632, Guangzhou, Guangdong, China.
  • 7 Department of Pathology, Medical School, Dalian University, 116622, Dalian, Liaoning, China. liushuangping@dlu.edu.cn.
  • 8 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, 301617, Tianjin, China. shuaizhang@tjutcm.edu.cn.
PMID: 31285420 DOI: 10.1038/s41419-019-1756-1
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.

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