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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2019

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Urinary Bladder Neoplasms
Epigenomics
NADP
Nucleotides
Aldehyde Oxidase
Kynurenine
Pentoses
Pentose Phosphate Pathway
Methyltransferases
Growth
Heterografts
Tryptophan
Neoplasms
Urinary Bladder
Epithelial Cells
Phosphates
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Vantaku, V., Putluri, V., Bader, D. A., Maity, S., Ma, J., Arnold, J. M., ... Putluri, N. (Accepted/In press). Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression. Oncogene. https://doi.org/10.1038/s41388-019-0902-7

Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression. / Vantaku, Venkatrao; Putluri, Vasanta; Bader, David A.; Maity, Suman; Ma, Jing; Arnold, James M.; Rajapakshe, Kimal; Donepudi, Sri Ramya; von Rundstedt, Friedrich Carl; Devarakonda, Vaishnavi; Dubrulle, Julien; Karanam, Balasubramanyam; McGuire, Sean E.; Stossi, Fabio; Jain, Abhinav K.; Coarfa, Cristian; Cao, Qi; Sikora, Andrew G.; Villanueva, Hugo; Kavuri, Shyam M.; Lotan, Yair; Sreekumar, Arun; Putluri, Nagireddy.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

Vantaku, V, Putluri, V, Bader, DA, Maity, S, Ma, J, Arnold, JM, Rajapakshe, K, Donepudi, SR, von Rundstedt, FC, Devarakonda, V, Dubrulle, J, Karanam, B, McGuire, SE, Stossi, F, Jain, AK, Coarfa, C, Cao, Q, Sikora, AG, Villanueva, H, Kavuri, SM, Lotan, Y, Sreekumar, A & Putluri, N 2019, 'Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression', Oncogene. https://doi.org/10.1038/s41388-019-0902-7
Vantaku, Venkatrao ; Putluri, Vasanta ; Bader, David A. ; Maity, Suman ; Ma, Jing ; Arnold, James M. ; Rajapakshe, Kimal ; Donepudi, Sri Ramya ; von Rundstedt, Friedrich Carl ; Devarakonda, Vaishnavi ; Dubrulle, Julien ; Karanam, Balasubramanyam ; McGuire, Sean E. ; Stossi, Fabio ; Jain, Abhinav K. ; Coarfa, Cristian ; Cao, Qi ; Sikora, Andrew G. ; Villanueva, Hugo ; Kavuri, Shyam M. ; Lotan, Yair ; Sreekumar, Arun ; Putluri, Nagireddy. / Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression. In: Oncogene. 2019.
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