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LincRNA PVT1 associates with EZH2 and with the androgen receptor in LNCaP prostate cancer cells and inhibits the expression of genes involved with cell death, cell differentiation and cell adhesion

ABSTRACT: Long intergenic non-coding RNA (lincRNA) PVT1 is an oncogene known to be overexpressed in various types of cancer. PVT1 high expression is associated with increased prostate cancer (PCa) risk while androgen-independent PCa progression is correlated with increased androgen receptor (AR) expression. However, the mechanism of PVT1 and AR involvement in the development of prostate cancer is still unclear. Here, we tested the hypothesis that PVT1 participates along with AR and the methyltransferase EZH2 from the Polycomb repressive complex 2 in the repression of gene expression in LNCaP prostate cancer cells. Native RNA-binding proteins immunoprecipitation followed by quantitative PCR of co-precipitated RNAs (RIP-qPCR) revealed that in LNCaP, PVT1 lincRNA is associated both with AR (10 – 12 % of PVT1 input) and EZH2 (36 – 42 % of input) in the presence or absence of androgen. PVT1 knockdown in LNCaP in the presence of androgen increased the expression of 160 genes whose expression was repressed by androgen, including genes involved in regulation of cell differentiation, in inhibition of cell migration/invasion and in triggering apoptosis. Analysis by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) of the histone marks occupancy at the promoter region of the tumor suppressor gene NOV, one of the genes that had an increased expression upon PVT1 silencing, showed a significant epigenetic remodeling at its promoter and enhancer regions upon PVT1 knockdown. We provide evidence for a genome-wide transcriptional repressive role of PVT1 lincRNA on tumor suppressor genes in prostate cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133372 | GEO | 2021/01/19

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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LincRNA PVT1 associates with EZH2 and with the androgen receptor in LNCaP prostate cancer cells and inhibits the expression of genes involved with cell death, cell differentiation and cell adhesion

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