Sarcosine is a prostate epigenetic modifier that elicits aberrant methylation patterns through the SAMe-Dnmts axis

Area of Science:

• Epigenetics
• Metabolomics
• Cancer Biology

Background:

• DNA hypermethylation is a common epigenetic alteration in prostate cancer (PCa).
• Sarcosine is identified as a PCa oncometabolite influencing malignant cell migration and proliferation.
• The precise mechanisms by which sarcosine affects prostate cancer cells remain incompletely understood.

Purpose of the Study:

• To investigate the epigenetic effects of sarcosine on prostate cells.
• To elucidate the role of sarcosine in regulating DNA methylation and associated enzymes.
• To determine if sarcosine's epigenetic modifications contribute to its oncometabolic function in PCa.

Main Methods:

• Incubation of prostate cell lines with sarcosine.
• Analysis of sarcosine N-demethylation enzyme activity (sarcosine dehydrogenase, pipecolic acid oxidase).
• Measurement of S-adenosylmethionine (SAMe) levels and cellular methylation potential.
• Global DNA methylation analysis (CpG islands).
• Assessment of DNA methyltransferase (DNMT) expression.
• Inhibition of DNMTs using 5-azacytidine.
• Spatial mapping of sarcosine, SAMe, and Dnmt1 in prostate tissue.

Main Results:

• Sarcosine exposure upregulated sarcosine N-demethylation enzymes and increased SAMe production and cellular methylation potential.
• Global DNA methylation analysis showed increased methylated CpG islands in prostate cells treated with sarcosine.
• Sarcosine treatment led to the upregulation of DNA methyltransferases (DNMTs).
• 5-azacytidine inhibited sarcosine-induced prostate cell migration by blunting DNMTs.
• Increased sarcosine, SAMe, and Dnmt1 were observed in malignant prostate tissue compared to nonmalignant tissue.

Conclusions:

• Sarcosine acts as an epigenetic modifier in prostate cells, increasing DNA methylation.
• Sarcosine upregulates DNMTs and enhances cellular methylation potential, potentially contributing to its oncometabolic role in PCa.
• These findings reveal a novel epigenetic mechanism linking sarcosine metabolism to prostate cancer progression.