DNA hypermethylation is one of the most common epigenetic modifications in prostate cancer (PCa). Several studies have delineated sarcosine as a PCa oncometabolite that increases the migration of malignant prostate cells while decreasing their doubling time. Here, we show that incubation of prostate cells with sarcosine elicited the upregulation of sarcosine N-demethylation enzymes, sarcosine dehydrogenase and pipecolic acid oxidase. This process was accompanied by a considerable increase in the production of the major methyl-donor S-adenosylmethionine (SAMe), together with an elevation of cellular methylation potential. Global DNA methylation analyses revealed increases in methylated CpG islands in distinct prostate cell lines incubated with sarcosine, but not in cells of nonprostate origin. This phenomenon was further associated with marked upregulation of DNA methyltransferases (Dnmts). Epigenetic changes were recapitulated through blunting of Dnmts using the hypomethylating agent 5-azacytidine, which was able to inhibit sarcosine-induced migration of prostate cells. Moreover, spatial mapping revealed concomitant increases in sarcosine, SAMe and Dnmt1 in histologically confirmed malignant prostate tissue, but not in adjacent or nonmalignant tissue, which is in line with the obtained in vitro data. In summary, we show here for the first time that sarcosine acts as an epigenetic modifier of prostate cells and that this may contribute to its oncometabolic role.

Central European Institute of Technology Brno University of Technology Czech Republic

Central European Institute of Technology Mendel University in Brno Czech Republic

Department of Biochemistry Faculty of Science Charles University Prague 2 Czech Republic

Department of Chemistry and Biochemistry Mendel University in Brno Czech Republic

Department of Food Chemistry and Toxicology Technical University of Berlin Germany

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University University Hospital Motol Prague 5 Czech Republic

Department of Pathology University Hospital Brno Czech Republic

Department of Urology University Hospital Brno Brno Czech Republic

Faculty of Medicine Masaryk University Brno Czech Republic

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