Abstract
The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.
Highlights
The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood
To define key biochemical pathways altered in prostate cancer (PCa), we used metabolomic and transcriptomic profiles from our previous study containing 12 treatment-naive localized PCa specimens and 16 benign adjacent prostate tissues (Ben)[10] (Supplementary Fig. 1A, clinical information in Supplementary Table 1) and integrated these using a novel pathway-centric analytical framework (Fig. 1a)
The modified Network-Based Gene Set Analysis (NetGSA) framework, unlike Gene set enrichment analysis (GSA)-type methods, incorporates reactome-derived interactions and associated stoichiometry between metabolites allowing for adequate statistical power[13]
Summary
To define key biochemical pathways altered in PCa, we used metabolomic and transcriptomic profiles from our previous study containing 12 treatment-naive localized PCa specimens and 16 benign adjacent prostate tissues (Ben)[10] (Supplementary Fig. 1A, clinical information in Supplementary Table 1) and integrated these using a novel pathway-centric analytical framework (Fig. 1a) This approach combines two rankings for each pathway calculated from gene expression and metabolic data, while adjusting for variations in each of the two data sets. Consistent with the findings in CRPC, transcript levels of HBP genes were significantly downregulated in CRPC tissues across multiple independent publically available microarray data sets (Supplementary Fig. 3B–E) Together, these results suggest significantly diminished activity of HBP in CRPC tumours compared with AD organ-confined PCa. HBP modulates aggressivity in CRPC. Riboflavin metabolism Biotin metabolism Aminosugar metabolism (HBP) Valine, leucine and isoleucine biosynthesis Cysteine metabolism
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