Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression.
Aldehyde Oxidase
/ genetics
Animals
Cell Line, Tumor
Disease Progression
Enhancer of Zeste Homolog 2 Protein
/ metabolism
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Kynurenine
/ metabolism
Male
Metabolomics
Mice
NADP
/ metabolism
Neoplasm Invasiveness
Neoplasm Staging
Nucleotides
/ biosynthesis
Pentose Phosphate Pathway
/ genetics
RNA-Seq
Tissue Array Analysis
Tryptophan
/ metabolism
Urinary Bladder
/ pathology
Urinary Bladder Neoplasms
/ genetics
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
04
03
2019
accepted:
05
04
2019
revised:
04
04
2019
pubmed:
7
8
2019
medline:
15
12
2020
entrez:
7
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31383940
doi: 10.1038/s41388-019-0902-7
pii: 10.1038/s41388-019-0902-7
pmc: PMC8058741
mid: NIHMS1660300
doi:
Substances chimiques
Nucleotides
0
Kynurenine
343-65-7
NADP
53-59-8
Tryptophan
8DUH1N11BX
AOX1 protein, human
EC 1.2.3.1
Aldehyde Oxidase
EC 1.2.3.1
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6265-6285Subventions
Organisme : NCI NIH HHS
ID : R01 CA133458
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056338
Pays : United States
Organisme : NIH HHS
ID : S10 OD020151
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216426
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167234
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220297
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Références
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.
doi: 10.1002/ijc.29210
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
doi: 10.3322/caac.21442
Sievert KD, Amend B, Nagele U, Schilling D, Bedke J, Horstmann M, et al. Economic aspects of bladder cancer: what are the benefits and costs? World J Urol. 2009;27:295–300.
pubmed: 19271220
pmcid: 2694315
Thoma C. Bladder cancer: genomics of noninvasive disease. Nat Rev Urol. 2018;15:1.
pubmed: 29205203
Hurst CD, Alder O, Platt FM, Droop A, Stead LF, Burns JE, et al. Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell. 2017;32:701–15 e7.
pubmed: 29136510
pmcid: 5774674
Garattini E, Fratelli M, Terao M. The mammalian aldehyde oxidase gene family. Hum Genom. 2009;4:119–30.
Garattini E, Fratelli M, Terao M. Mammalian aldehyde oxidases: genetics, evolution and biochemistry. Cell Mol Life Sci. 2008;65:1019–48.
pubmed: 18066686
Kitamura S, Sugihara K, Ohta S. Drug-metabolizing ability of molybdenum hydroxylases. Drug Metab Pharm. 2006;21:83–98.
Putluri N, Shojaie A, Vasu VT, Vareed SK, Nalluri S, Putluri V, et al. Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression. Cancer Res. 2011;71:7376–86.
pubmed: 3249241
pmcid: 3249241
Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–96.
pubmed: 9338076
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, et al. 5’ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1:686–92.
pubmed: 7585152
Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, et al. Hypermethylation-associated inactivation ofp14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res. 2000;60:129–33.
pubmed: 10646864
Di Croce L, Helin K. Transcriptional regulation by Polycomb group proteins. Nat Struct Mol Biol. 2013;20:1147–55.
pubmed: 24096405
Sun S, Yu F, Zhang L, Zhou X. EZH2, an on-off valve in signal network of tumor cells. Cell Signal. 2016;28:481–7.
pubmed: 26876615
Ma J, Shojaie A, Michailidis G. Network-based pathway enrichment analysis with incomplete network information. Bioinformatics. 2016;32:3165–74.
pubmed: 27357170
pmcid: 5939912
Kim WJ, Kim EJ, Kim SK, Kim YJ, Ha YS, Jeong P, et al. Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer. Mol Cancer. 2010;9:3.
pubmed: 20059769
pmcid: 2821358
Cancer Genome Atlas Research Network Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.
Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 2006;24:778–89.
pubmed: 16432078
Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25:152–65.
pubmed: 24525232
pmcid: 4011497
McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.
pubmed: 23051747
pmcid: 23051747
Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–4.
pubmed: 16357870
Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003;100:11606–11.
pubmed: 14500907
pmcid: 208805
Oster B, Thorsen K, Lamy P, Wojdacz TK, Hansen LL, Birkenkamp-Demtroder K, et al. Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas. Int J Cancer. 2011;129:2855–66.
pubmed: 21400501
Salter M, Pogson CI. The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Effects of glucocorticoids and experimental diabetes. Biochem J. 1985;229:499–504.
pubmed: 3899109
pmcid: 1145083
D’Amato NC, Rogers TJ, Gordon MA, Greene LI, Cochrane DR, Spoelstra NS, et al. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res. 2015;75:4651–64.
pubmed: 26363006
pmcid: 4631670
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.
pubmed: 18539112
De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110.
pubmed: 23344542
Deryugina EI, Quigley JP. Chick embryo chorioallantoic membrane model systems to study and visualize human tumor cell metastasis. Histochem Cell Biol. 2008;130:1119–30.
pubmed: 19005674
pmcid: 2699943
Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, Zwarthoff EC. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS ONE. 2010;5:e13821.
pubmed: 21072204
pmcid: 2972209
Vantaku V, Dong J, Ambati CR, Perera D, Donepudi SR, Amara CS, et al. Multi-omics integration analysis robustly predicts high-grade patient survival and identifies CPT1B effect on fatty acid metabolism in Bladder Cancer. Clin Cancer Res. 2019;15:3689–701.
Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72:5435–40.
pubmed: 23090118
Ablain J, de The H. Retinoic acid signaling in cancer: the parable of acute promyelocytic leukemia. Int J Cancer. 2014;135:2262–72.
pubmed: 25130873
Yang M, Pollard PJ. Succinate: a new epigenetic hacker. Cancer Cell. 2013;23:709–11.
pubmed: 23763995
Zhai L, Spranger S, Binder DC, Gritsina G, Lauing KL, Giles FJ, et al. Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin Cancer Res. 2015;21:5427–33.
pubmed: 26519060
pmcid: 4681601
Icard P, Poulain L, Lincet H. Understanding the central role of citrate in the metabolism of cancer cells. Biochim Biophys Acta. 2012;1825:111–6.
pubmed: 22101401
Ozturk S, Papageorgis P, Wong CK, Lambert AW, Abdolmaleky HM, Thiagalingam A, et al. SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis. Proc Natl Acad Sci USA. 2016;113:638–43.
pubmed: 26739564
pmcid: 4725521
Haldrup C, Mundbjerg K, Vestergaard EM, Lamy P, Wild P, Schulz WA, et al. DNA methylation signatures for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer. J Clin Oncol. 2013;31:3250–8.
pubmed: 23918943
Park JS, Choi SB, Chung JW, Kim SW, Kim DW. Classification of serous ovarian tumors based on microarray data using multicategory support vector machines. Conf Proc IEEE Eng Med Biol Soc. 2014;2014:3430–3.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.
pubmed: 12374981
Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006;24:268–73.
pubmed: 16330673
Sudo T, Utsunomiya T, Mimori K, Nagahara H, Ogawa K, Inoue H, et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer. 2005;92:1754–8.
pubmed: 15856046
pmcid: 2362028
Hussain M, Rao M, Humphries AE, Hong JA, Liu F, Yang M, et al. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res. 2009;69:3570–8.
pubmed: 19351856
Yan J, Ng SB, Tay JL, Lin B, Koh TL, Tan J, et al. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood. 2013;121:4512–20.
pubmed: 23529930
Tan JZ, Yan Y, Wang XX, Jiang Y, Xu HE. EZH2: biology, disease, and structure-based drug discovery. Acta Pharmacol Sin. 2014;35:161–74.
pubmed: 24362326
The EZH2 Inhibitor Tazemetostat Is Well Tolerated in a Phase I Trial. Cancer Discov. 2018;8:OF15. http://cancerdiscovery.aacrjournals.org/content/early/2018/04/20/2159-8290.CD-RW2018-067 , https://doi.org/10.1158/2159-8290.CD-RW2018-067 . Accessed 9 Apr 2018.
Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.
pubmed: 26845405
pmcid: 4918227
Dudziec E, Goepel JR, Catto JW. Global epigenetic profiling in bladder cancer. Epigenomics. 2011;3:35–45.
pubmed: 22126151
Reinert T, Modin C, Castano FM, Lamy P, Wojdacz TK, Hansen LL, et al. Comprehensive genome methylation analysis in bladder cancer: identification and validation of novel methylated genes and application of these as urinary tumor markers. Clin Cancer Res. 2011;17:5582–92.
pubmed: 21788354
Wolff EM, Chihara Y, Pan F, Weisenberger DJ, Siegmund KD, Sugano K, et al. Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue. Cancer Res. 2010;70:8169–78.
pubmed: 20841482
pmcid: 2955801
Agledal L, Niere M, Ziegler M. The phosphate makes a difference: cellular functions of NADP. Redox Rep. 2010;15:2–10.
pubmed: 20196923
Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008;10:179–206.
pubmed: 18020963
Prendergast GC. Cancer: why tumours eat tryptophan. Nature. 2011;478:192–4.
pubmed: 21993754
Chen Y, Guillemin GJ. Kynurenine pathway metabolites in humans: disease and healthy States. Int J Tryptophan Res. 2009;2:1–19.
pubmed: 22084578
pmcid: 3195227
Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015;15:608–24.
pubmed: 26383140
Beaconsfield P, Ginsburg J, Jeacock MK. Glucose metabolism via the pentose phosphate pathway relative to nucleic acid and protein synthesis in the human placenta. Dev Med Child Neurol. 1964;6:469–74.
pubmed: 14215224
Davidson B, Abeler VM, Forsund M, Holth A, Yang Y, Kobayashi Y, et al. Gene expression signatures of primary and metastatic uterine leiomyosarcoma. Hum Pathol. 2014;45:691–700.
pubmed: 24485798
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478:197–203.
pubmed: 21976023
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24.
pubmed: 16049480
pmcid: 1283098
Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459:1005–9.
pubmed: 19421193
pmcid: 2698953
Jin F, Thaiparambil J, Donepudi SR, Vantaku V, Piyarathna DWB, Maity S, et al. Tobacco-specific carcinogens induce hypermethylation, DNA adducts, and DNA damage in bladder cancer. Cancer Prev Res. 2017;10:588–97.
Piyarathna DWB, Rajendiran TM, Putluri V, Vantaku V, Soni T, von Rundstedt FC, et al. Distinct lipidomic landscapes associated with clinical stages of urothelial cancer of the bladder. Eur Urol Focus. 2018;4:907–915.
Terunuma A, Putluri N, Mishra P, Mathe EA, Dorsey TH, Yi M, et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014;124:398–412.
pubmed: 24316975
Putluri N, Maity S, Kommagani R, Creighton CJ, Putluri V, Chen F, et al. Pathway-centric integrative analysis identifies RRM2 as a prognostic marker in breast cancer associated with poor survival and tamoxifen resistance. Neoplasia. 2014;16:390–402.
pubmed: 4198742
pmcid: 4198742
Putluri N, Shojaie A, Vasu VT, Nalluri S, Vareed SK, Putluri V, et al. Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells. PLoS ONE. 2011;6:e21417.
pubmed: 21789170
pmcid: 3138744
Bhowmik SK, Ramirez-Pena E, Arnold JM, Putluri V, Sphyris N, Michailidis G, et al. EMT-induced metabolite signature identifies poor clinical outcome. Oncotarget. 2015;6:42651–60.
pubmed: 4767460
pmcid: 4767460
Estecio MR, Yan PS, Ibrahim AE, Tellez CS, Shen L, Huang TH, et al. High-throughput methylation profiling by MCA coupled to CpG island microarray. Genome Res. 2007;17:1529–36.
pubmed: 17785535
pmcid: 1987348
Blecher-Gonen R, Barnett-Itzhaki Z, Jaitin D, Amann-Zalcenstein D, Lara-Astiaso D, Amit I. High-throughput chromatin immunoprecipitation for genome-wide mapping of in vivo protein-DNA interactions and epigenomic states. Nat Protoc. 2013;8:539–54.
pubmed: 23429716
O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–85.
pubmed: 9008168
Li M, Pathak RR, Lopez-Rivera E, Friedman SL, Aguirre-Ghiso JA, Sikora AG. The in ovo chick chorioallantoic membrane (CAM) assay as an efficient xenograft model of hepatocellular carcinoma. J Vis Exp. 2015.