Changliang Shan

HPD is an RNA‐Binding Protein Sustaining Ovarian Cancer Cell Glycolysis, Tumor Growth, and Drug Resistance

Abstract 4‐hydroxyphenylpyruvate dioxygenase (HPD) is an important metabolic enzyme in the tyrosine metabolic pathway and displays aberrant expression and function in cancer. Unexpectedly, it is discovered that HPD functions as an RNA‐binding protein (RBP) to drive ovarian cancer progression. HPD is shown to bind to the RRACH motif of these target mRNAs through its two dsRNA binding domains (RBDs), resulting in increased global mRNA translation. In particular, HPD binding is demonstrated to mediate translation of glycolytic enzymes triosephosphate isomerase (TPI) and alpha‐enolase (ENO1) mRNAs, which facilitates ovarian cancer glycolysis and tumor growth. Thus, targeting the RBD domain of HPD disrupts its RNA binding ability, leading to blocking glycolysis flux, tumor growth, and enhancing drug response. HPD is a novel RNA‐binding protein, and this moonlighting function highlights the knowledge of HPD in regulating cancer development and drug response beyond only as a metabolic enzyme.

Discovery and characterization of a novel glucose-6-phosphate dehydrogenase (G6PD) inhibitor via high-throughput screening

Altered glucose-6-phosphate dehydrogenase (G6PD) status is influential in many cellular pathophysiological processes and diseases, making G6PD a potential target for cancer therapy. However, the available G6PD inhibitors are very limited and restricted. Here we developed a reducing equivalent nicotinamide adenine dinucleotide phosphate (NADPH) absorption photometry assay based on enzyme kinetics to characterize G6PD activity. In this way, we performed a high-throughput screening (HTS) to an in house library. And then we identified compound named Wedelolactone inhibiting G6PD strongly in a non-competitive, reversible way. In addition, we did the surface Plasmon Resonance (SPR) assay and indicated the K