The Role And Mechanism Of HPD On Regulating Lung Cancer Cell Metabolism And Cell Proliferation

Lung cancer is one of the common malignancies in the world,reprogramming of energy metabolism has been recognized as an emerging hallmark of cancer.The Warburg effect describes the observation that cancer cells undergo metabolism reprogramming marked by increased in aerobic glycolysis and elevated lactate production,which generates more ATPs more quickly than in normal cells that overwhelmingly rely on oxidative phosphorylation.Besides the dysregulation of glucose metabolism,metabolic reprogramming in cancer cells has been characterized by aberrant lipid metabolism,amino acids metabolism,mitochondrial biogenesis,and other bioenergetic metabolism pathways.Investigation on these energy metabolism reprogramming would uncover fundamental molecular events of malignancy and help to find better ways to diagnose and treat cancer.The 4-hydroxyphenylpyruvate dioxygenase(HPD)is a key enzyme in tyrosine metabolism,which deficient can cause tyrosinemia.But the precise contribution of HPD to cancer metabolism and tumorgenesis remains unclear.Here we report that suppression of HPD in cancer cells resulted in reduced oxidative pentose phosphate pathway(PPP)flux in addition to reduced RNA biosynthesis and elevated ROS levels,attenuating cancer cell proliferation and tumor growth.In this context,there are two supposed scenarios for G6 PD regulation by HPD.The first possibility is that HPD promotes tyrosine catabolism lead to increase Acetyl-Co A levels,which result in increase H3 acetylation levels,then upregulate G6 PD express.The secondly possibility is that HPD-mediated AMPK activation by the active LKB1 complex,leading to phosphorylation of Histone deacetylase 10 and subsequent increase G6 PD express.Thus,the LKB1-AMPK-HDAC10 axis strongly links oxidative PPP and tyrosine metabolism and may become a promising cancer therapeutic target.