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

Changliang Shan,Shuangping Liu,Shuai Zhang,Hao Sheng,Zhen Li,Zhaoliang Lu,Jun Fan,Qi Qi

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.

Highlights

Lung cancer is the leading cause of cancer mortality, which ranks as the first cancer-related mortality worldwide
hydroxyphenylpyruvate dioxygenase (HPD) promotes cell proliferation and tumor growth in vitro and in vivo To determine the role of HPD in lung cancer, we first examined the expression of HPD in tissues from lung cancer patients
HPD has been considered an important disease gene, whose deficiency and single mutation in the Nterminal region produces Type III tyrosinemia leading to hawkinsinuria[18,20], its contribution to cell metabolism and tumor formation is not defined

Summary

Introduction

Lung cancer is the leading cause of cancer mortality, which ranks as the first cancer-related mortality worldwide. Few symptoms during early disease stages, and metastasis to other organs before diagnosis, there is a critical need to elucidate the underlying molecular mechanisms and identify molecular targets in lung cancer. Studies report that metabolic enzymes play an important role in cancer cell metabolism and tumorigenesis[1,2]. Besides glucose anaerobic metabolism (known as Warburg effect), emerging evidence indicates that metabolism of other nutrients, such as glutamine, fatty acids, cholesterol, amino acids, and one carbon, is important for tumor proliferation[3,4,5,6,7,8,9]. Identifying the roles of metabolic enzymes involved in nutrient metabolism is required in order to uncover fundamental molecular events of malignancy and reveal new targets for cancer diagnosis and treatment

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Conclusion