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. Kavuri; Yair Lotan; Arun Sreekumar; Nagireddy Putluri

doi:10.1038/s41388-019-0902-7

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^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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 language	English (US)
Pages (from-to)	6265-6285
Number of pages	21
Journal	Oncogene
Volume	39
Issue number	40
DOIs	https://doi.org/10.1038/s41388-019-0902-7
State	Published - Oct 1 2020

Funding

Acknowledgements This research was fully supported by American Cancer Society (ACS) Award 127430-RSG-15-105-01-CNE (N.P.), NIH/NCI R01CA220297 (N.P), and NIH/NCI R01CA216426 (N.P.), partially supported by the following grants: NIH 1RO1CA133458-01 (A.S.K.), and NIH U01 CA167234, Komen CCR award to S.M.K. (CCR16380599) as well as funds from Alkek Center for Molecular Discovery (A.S.K.). This project was also supported by the Agilent Technologies Center of Excellence in Mass Spectrometry at Baylor College of Medicine, Metabolomics Core, Human Tissue Acquisition and Pathology at Baylor College of Medicine with funding from the NIH (P30 CA125123), CPRIT Proteomics and Metabolomics Core Facility (D.P.E.), (RP170005), and Dan L. Duncan Cancer Center. Imaging for this project was supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from NIH (DK56338, CA125123, and 1S10OD020151-01), CPRIT (RP150578), the Dan L. Duncan Comprehensive Cancer Center, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. CAM assay was supported by the Patient-Derived Xenograft and Advanced in vivo Models Core Facility at Baylor College of Medicine with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) grant #170691. Imaging for this project was supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from NIH (DK56338, and CA125123), CPRIT (RP150578, RP170719), the Dan L. Duncan Comprehensive Cancer Center, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. Research reported in this study was supported by the National Cancer Institute of the National Institutes of Health under award number 5 P30 CA142543 09.

ASJC Scopus subject areas

Genetics
Molecular Biology
Cancer Research

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Vantaku, V., Putluri, V., Bader, D. A., Maity, S., Ma, J., Arnold, J. M., Rajapakshe, K., Donepudi, S. R., von Rundstedt, F. C., Devarakonda, V., Dubrulle, J., Karanam, B., McGuire, S. E., Stossi, F., Jain, A. K., Coarfa, C., Cao, Q., Sikora, A. G., Villanueva, H., ... Putluri, N. (2020). Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression. Oncogene, 39(40), 6265-6285. https://doi.org/10.1038/s41388-019-0902-7

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

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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 2020, 'Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression', Oncogene, vol. 39, no. 40, pp. 6265-6285. https://doi.org/10.1038/s41388-019-0902-7

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T1 - Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression

AU - Vantaku, Venkatrao

AU - Putluri, Vasanta

AU - Bader, David A.

AU - Maity, Suman

AU - Ma, Jing

AU - Arnold, James M.

AU - Rajapakshe, Kimal

AU - Donepudi, Sri Ramya

AU - von Rundstedt, Friedrich Carl

AU - Devarakonda, Vaishnavi

AU - Dubrulle, Julien

AU - Karanam, Balasubramanyam

AU - McGuire, Sean E.

AU - Stossi, Fabio

AU - Jain, Abhinav K.

AU - Coarfa, Cristian

AU - Cao, Qi

AU - Sikora, Andrew G.

AU - Villanueva, Hugo

AU - Kavuri, Shyam M.

AU - Lotan, Yair

AU - Sreekumar, Arun

AU - Putluri, Nagireddy

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

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

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