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

by Stossi Fabio , Sikora, Andrew G , Bader, David A , Kimal, Rajapakshe , Friedrich-Carl, von Rundstedt , Coarfa Cristian , Devarakonda Vaishnavi , Kavuri, Shyam M , Sreekumar Arun , Dubrulle Julien , Ma, Jing , Lotan Yair , Vasanta, Putluri , Jain, Abhinav K , Nagireddy, Putluri , Arnold, James M , McGuire, Sean E , Balasubramanyam, Karanam , Cao Qi , Villanueva, Hugo , Donepudi Sri Ramya , Venkatrao, Vantaku , Maity Suman

in Aldehyde oxidase / Bladder cancer / Cell culture / Epigenetics / Epithelial cells / Metabolic flux / Metabolic rate / Metabolism / Metabolites / Methyltransferase / NADP / Pentose phosphate pathway / Tryptophan / Xenografts

2020

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

2020

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2020

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Journal Article

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

Stossi Fabio,

Sikora, Andrew G,

Bader, David A,

Kimal, Rajapakshe,

Friedrich-Carl, von Rundstedt,

Coarfa Cristian,

Devarakonda Vaishnavi,

Kavuri, Shyam M,

Sreekumar Arun,

Dubrulle Julien,

Ma, Jing,

Lotan Yair,

Vasanta, Putluri,

Jain, Abhinav K,

Nagireddy, Putluri,

Arnold, James M,

McGuire, Sean E,

Balasubramanyam, Karanam,

Cao Qi,

Villanueva, Hugo,

Donepudi Sri Ramya,

Venkatrao, Vantaku,

Maity Suman

2020

Overview

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.

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