A novel metabolic function of Myc in regulation of fatty acid synthesis in prostate cancer

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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Fig. 1: MYC expression is positively correlated with that of key genes involved in fatty acid synthesis in prostate cancer TCGA.
Fig. 2: Expression of proteins responsible for fatty acid synthesis is increased in prostatic intraepithelial neoplasia (PIN) and adenocarcinoma (ADC) by prostate-specific transgenic expression of Myc in Hi-Myc mice.
Fig. 3: Circulating levels of total free fatty acids and their metabolic intermediaries is increased by prostate-specific transgenic expression of Myc in Hi-Myc mice.
Fig. 4: Expression of fatty acid synthesis proteins in normal and cancerous human prostate.
Fig. 5: Association of Myc protein expression with that of ACLY or ACC1 in normal and cancerous human prostate.

Data availability

The data and material generated for this study are available upon request to the corresponding author.

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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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Correspondence to Shivendra V. Singh.

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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 (2020). https://doi.org/10.1038/s41388-020-01553-z

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