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Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression.

Venkatrao VantakuVasanta PutluriDavid A BaderSuman MaityJing MaJames M ArnoldKimal RajapaksheSri Ramya DonepudiFriedrich-Carl von RundstedtVaishnavi DevarakondaJulien DubrulleBalasubramanyam KaranamSean E McGuireFabio StossiAbhinav K JainCristian CoarfaQi CaoAndrew G SikoraHugo VillanuevaShyam M KavuriYair LotanArun SreekumarNagireddy Putluri
Published in: Oncogene (2019)
Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA and our findings demonstrate that AOX1 is epigenetically silenced during BLCA progression by the methyltransferase activity of EZH2. Knockdown (KD) of AOX1 in normal bladder epithelial cells re-wires the tryptophan-kynurenine pathway resulting in elevated NADP levels which may increase metabolic flux through the pentose phosphate (PPP) pathway, enabling increased nucleotide synthesis, and promoting cell invasion. Inhibition of NADP synthesis rescues the metabolic effects of AOX1 KD. Ectopic AOX1 expression decreases NADP production, PPP flux and nucleotide synthesis, while decreasing invasion in cell line models and suppressing growth in tumor xenografts. Further gain and loss of AOX1 confirm the EZH2-dependent activation, metabolic deregulation, and tumor growth in BLCA. Our findings highlight the therapeutic potential of AOX1 and provide a basis for the development of prognostic markers for advanced BLCA.
Keyphrases
  • poor prognosis
  • long noncoding rna
  • long non coding rna
  • gene expression
  • dna methylation
  • spinal cord injury
  • ms ms
  • signaling pathway