Abstract
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.
Highlights
Chromatin structure defines the state in which genetic information in the form of DNA is organized (Toh et al, 2017)
We examined the expression of dimethylglycine dehydrogenase (DMGDH), which is involved in the subpathway that synthesizes sarcosine from dimethylglycine, and pipecolic acid oxidase (PIPOX), which catalyses the oxidative demethylation of sarcosine to yield glycine
Together with HPLC-fluorescence detection (FLD) that revealed a rapid intracellular accumulation of sarcosine (Table S3), the obtained data indicate that the addition of sarcosine increases its intracellular pool, which leads to the consequent upregulation of sarcosine dehydrogenase (SARDH) and PIPOX, enzymes mediating sarcosine N-demethylation
Summary
Chromatin structure defines the state in which genetic information in the form of DNA is organized (Toh et al, 2017). Recent advances in cancer research have shown that global changes in the epigenetic landscape are a hallmark of various types of malignant diseases, including prostate cancer (PCa) (Jeronimo et al, 2011; Jones and Baylin, 2002, 2007). DNA hypermethylation is one of the most common in PCa (Dobosy et al, 2007; Geybels et al, 2015; Hoque et al, 2005). The hypermethylation of regions with a high G/C content (palindromic CpG islands) of tumour suppressor genes leads to their inactivation, which may represent an early event in PCa development (Valdes-Mora and Clark, 2015)
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