Pathway based integrative analysis reveals a key role for the hexosamine biosynthetic pathway in prostate cancer progression with therapeutic implications

To better understand the biochemical changes associated with castrate resistant prostate cancer (CRPC), we developed a pathway-based integrated analytical method to examine prostate cancer (PCa) gene expression and metabolomic datasets and found distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) between androgen dependent (AD) PCa and CRPC, with elevated expression of HBP genes in primary PCa associated with poor clinical outcome. Expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in AD PCa while relatively diminished in CRPC.Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased aggressiveness, while GNPNAT1 knockdown decreased proliferation in AD PCa cells. Each scenario was accompanied by specific bio-energetic and molecular alterations. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine significantly enhanced efficacy of the anti-androgen enzalutamide in CRPC cells by repressing NF-Y driven cell cycle regulators. Our study demonstrates the therapeutic value of targeting altered metabolic pathways in lethal PCa. 1. Metabolic therapy approach was used where C4-2 cells were treated with PBS, UDP-N-acetylglucosamine (UDP-GlcNAc), MDV3100, UDP-GlcNAc+MDV3100. The expression of these cells were generated using Human Affymetrix Gene ST 2.1 2. Affimatrix platform based microarray was also done on GNPNAT1 Knockdow C42 cells.