Abstract
A subset of human prostate cancer exhibits increased de novo synthesis of fatty acids, but the molecular driver(s) of this metabolic abnormality remains obscure. This study demonstrates a novel metabolic function of c-Myc (Myc) in regulation of fatty acid synthesis. The role of Myc in regulation of fatty acid synthesis was investigated by: (a) interrogation of the prostate cancer The Cancer Genome Atlas (TCGA) dataset, (b) chromatin immunoprecipitation, and (c) determination of the expression of fatty acid synthesis enzymes and targeted metabolomics using a mouse model and human specimens. The expression of MYC was positively associated with that of key fatty acid synthesis genes including ACLY, ACC1, and FASN in prostate cancer TCGA dataset. Chromatin immunoprecipitation revealed Myc occupancy at the promoters of ACLY, ACC1, and FASN. Prostate-specific overexpression of Myc in Hi-Myc transgenic mice resulted in overexpression of ACLY, ACC1, and FASN proteins in neoplastic lesions and increased circulating levels of total free fatty acids. Targeted metabolomics confirmed increased circulating levels of individual fatty acids in the plasma of Hi-Myc mice and human subjects when compared to corresponding controls. Immunohistochemistry also revealed a positive and statistically significant association in expression of Myc with that of ACC1 in human prostate adenocarcinoma specimens. We propose that Myc-regulated fatty acid synthesis is a valid target for therapy and/or prevention of prostate cancer.
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The data and material generated for this study are available upon request to the corresponding author.
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.
Sun J, Liu W, Adams TS, Sun J, Li X, Turner AR, et al. DNA copy number alterations in prostate cancers: a combined analysis of published CGH studies. Prostate. 2007;67:692–700.
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.
Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–43.
Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol. 2011;29:3659–68.
He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, Meissner PS, et al. A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics. 1997;43:69–77.
Jenkins RB, Qian J, Lieber MM, Bostwick DG. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res. 1997;57:524–31.
Wang SI, Parsons R, Ittmann M. Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin Cancer Res. 1998;4:811–5.
Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell. 2003;4:223–38.
Buttyan R, Sawczuk IS, Benson MC, Siegal JD, Olsson CA. Enhanced expression of the c-myc protooncogene in high-grade human prostate cancers. Prostate. 1987;11:327–37.
Nag A, Smith RG. Amplification, rearrangement, and elevated expression of c-myc in the human prostatic carcinoma cell line LNCaP. Prostate. 1989;15:115–22.
Edwards J, Krishna NS, Witton CJ, Bartlett JM. Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin Cancer Res. 2003;9:5271–81.
Gurel B, Iwata T, Koh CM, Jenkins RB, Lan F, Van Dang C, et al. Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod Pathol. 2008;21:1156–67.
Fox SB, Persad RA, Royds J, Kore RN, Silcocks PB, Collins CC. p53 and c-myc expression in stage A1 prostatic adenocarcinoma: useful prognostic determinants? J Urol. 1993;150:490–4.
Zeng W, Sun H, Meng F, Liu Z, Xiong J, Zhou S, et al. Nuclear C-MYC expression level is associated with disease progression and potentially predictive of two year overall survival in prostate cancer. Int J Clin Exp Pathol. 2015;8:1878–88.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Wu X, Daniels G, Lee P, Monaco ME. Lipid metabolism in prostate cancer. Am J Clin Exp Urol. 2014;2:111–20.
Suburu J, Chen YQ. Lipids and prostate cancer. Prostaglandins Other Lipid Mediat. 2012;98:1–10.
Liu Y. Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis. 2006;9:230–4.
Chavarro JE, Kenfield SA, Stampfer MJ, Loda M, Campos H, Sesso HD, et al. Blood levels of saturated and monounsaturated fatty acids as markers of de novo lipogenesis and risk of prostate cancer. Am J Epidemiol. 2013;178:1246–55.
Priolo C, Pyne S, Rose J, Regan ER, Zadra G, Photopoulos C, et al. AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer. Cancer Res. 2014;74:7198–204.
Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–70.
Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA. 1997;94:6658–63.
Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov. 2015;5:1024–39.
Rossi S, Graner E, Febbo P, Weinstein L, Bhattacharya N, Onody T, et al. Fatty acid synthase expression defines distinct molecular signatures in prostate cancer. Mol Cancer Res. 2003;1:707–15.
Shimano H. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res. 2001;40:439–52.
Schmidt LJ, Tindall DJ. Androgen receptor: past, present and future. Curr Drug Targets. 2013;14:401–7.
Miyoshi Y, Uemura H, Fujinami K, Mikata K, Harada M, Kitamura H, et al. Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients. Prostate. 2000;43:225–32.
Gao L, Schwartzman J, Gibbs A, Lisac R, Kleinschmidt R, Wilmot B, et al. Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation. PLoS ONE. 2013;8:e63563.
Swinnen JV, Van Veldhoven PP, Esquenet M, Heyns W, Verhoeven G. Androgens markedly stimulate the accumulation of neutral lipids in the human prostatic adenocarcinoma cell line LNCaP. Endocrinology. 1996;137:4468–74.
Gouw AM, Margulis K, Liu NS, Raman SJ, Mancuso A, Toal GG, et al. The MYC oncogene cooperates with sterol-regulated element-binding protein to regulate lipogenesis essential for neoplastic growth. Cell Metab. 2019;30:556–72.e555.
Zhang Q, Yin X, Pan Z, Cao Y, Han S, Gao G, et al. Identification of potential diagnostic and prognostic biomarkers for prostate cancer. Oncol Lett. 2019;18:4237–45.
Gao Y, Islam MS, Tian J, Lui VW, Xiao D. Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth. Cancer Lett. 2014;349:15–25.
Scott KE, Wheeler FB, Davis AL, Thomas MJ, Ntambi JM, Seals DF, et al. Metabolic regulation of invadopodia and invasion by acetyl-CoA carboxylase 1 and de novo lipogenesis. PLoS ONE. 2012;7:e29761.
Shah US, Dhir R, Gollin SM, Chandran UR, Lewis D, Acquafondata M, et al. Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. Hum Pathol. 2006;37:401–9.
Chen HW, Chang YF, Chuang HY, Tai WT, Hwang JJ. Targeted therapy with fatty acid synthase inhibitors in a human prostate carcinoma LNCaP/tk-luc-bearing animal model. Prostate Cancer Prostatic Dis. 2012;15:260–4.
Migita T, Ruiz S, Fornari A, Fiorentino M, Priolo C, Zadra G, et al. Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst. 2009;101:519–32.
Singh KB, Kim SH, Hahm ER, Pore SK, Jacobs BL, Singh SV. Prostate cancer chemoprevention by sulforaphane in a preclinical mouse model is associated with inhibition of fatty acid metabolism. Carcinogenesis. 2018;39:826–37.
Singh KB, Hahm ER, Pore SK, Singh SV. Leelamine is a novel lipogenesis inhibitor in prostate cancer cells in vitro and in vivo. Mol Cancer Ther. 2019;18:1800–10.
Vyas AR, Moura MB, Hahm ER, Singh KB, Singh SV. Sulforaphane inhibits c-Myc-mediated prostate cancer stem-like traits. J Cell Biochem. 2016;117:2482–95.
Singh KB, Hahm ER, Alumkal JJ, Foley LM, Hitchens TK, Shiva SS, et al. Reversal of the Warburg phenomenon in chemoprevention of prostate cancer by sulforaphane. Carcinogenesis. 2019;40:1545–56.
Li X, Franke AA. Improved LC-MS method for the determination of fatty acids in red blood cells by LC-orbitrap MS. Anal Chem. 2011;83:3192–8.
Funding
This study was supported by the National Cancer Institute grant R01 CA225716 (to S.V.S.). This study used the Animal Facility and the Tissue and Research Pathology Facility partly supported by the National Cancer Institute grant P30 CA047904. The funders had no role in the design of the study, data collection, analysis or interpretation of the data, manuscript preparation or decision to submit the manuscript for publication.
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KBS, ERH, SHK, and/or SVS conceived the study, performed experiments, interpreted the results, and wrote the manuscript. SWG performed targeted metabolomics. All authors reviewed and approved the final manuscript.
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Singh, K.B., Hahm, ER., Kim, SH. et al. A novel metabolic function of Myc in regulation of fatty acid synthesis in prostate cancer. Oncogene 40, 592–602 (2021). https://doi.org/10.1038/s41388-020-01553-z
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DOI: https://doi.org/10.1038/s41388-020-01553-z
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