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PiR-hsa-4447944 serves as an oncogenic mediator in prostate cancer and promotes the development of castration resistance by inhibiting NEFH expression

ABSTRACT: PiR-hsa-4447944 showed a significantly higher expression level in both CRPC tissues and CRPC cell lines. Functionally, piR-hsa-4447944 overexpression conferred, whereas piR-hsa-4447944 suppression inhibited castration resistance ability in vitro and in vivo. Enforced piR-hsa-4447944 expression in vitro promoted PCa cells migration and invasion, as well as reduced cell apoptosis. To explore the potential targets of piR-hsa-4447944, two PCa cells 22RV1 and LNCaP were transfected with control or piR-hsa-4447944 mimic, and then the extracted total RNA was used for mRNA sequencing and bioinformatic analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248169 | GEO | 2024/07/17

REPOSITORIES: GEO

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Project description:The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells GNPNAT1 expression was knockdown in two independent prostate cancer cells, 22Rv1 and LNCaP-ABL

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PiR-hsa-4447944 serves as an oncogenic mediator in prostate cancer and promotes the development of castration resistance by inhibiting NEFH expression

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