Abstract
S-adenosyl methionine (SAM) is a ubiquitous methyl donor that was reported to have chemo- protective activity against liver cancer, however the molecular footprint of SAM is unknown. We show here that SAM selectively inhibits growth, transformation and invasiveness of hepatocellular carcinoma cell lines but not normal primary liver cells. Analysis of the transcriptome of SAM treated and untreated liver cancer cell lines HepG2 and SKhep1 and primary liver cells reveals pathways involved in cancer and metastasis that are upregulated in cancer cells and are downregulated by SAM. Analysis of the methylome using bisulfite mapping of captured promoters and enhancers reveals that SAM hyper-methylates and downregulates genes in pathways of growth and metastasis that are upregulated in liver cancer cells. Depletion of two SAM downregulated genes STMN1 and TAF15 reduces cellular transformation and invasiveness, providing evidence that SAM targets are genes important for cancer growth and invasiveness. Taken together these data provide a molecular rationale for SAM as an anticancer agent.
Highlights
Broad changes in DNA methylation are a hallmark of cancer and are hypothesized to play a role in cancer initiation, progression and metastasis [1, 2]
Analysis of the transcriptome of S-adenosyl methionine (SAM) treated and untreated liver cancer cell lines HepG2 and SKhep1 and primary liver cells reveals pathways involved in cancer and metastasis that are upregulated in cancer cells and are downregulated by SAM
Analysis of the methylome using bisulfite mapping of captured promoters and enhancers reveals that SAM hyper-methylates and downregulates genes in pathways of growth and metastasis that are upregulated in liver cancer cells
Summary
Broad changes in DNA methylation are a hallmark of cancer and are hypothesized to play a role in cancer initiation, progression and metastasis [1, 2]. Changes in DNA methylation in cancer cells include both increase in DNA methylation in promoters of many genes as well as reduced methylation in repetitive sequences and promoters of genes [1]. Studies revealed that hypomethylation of promoters of genes that are important for cancer metastasis is a common feature of cancer [3, 4] i.e. Heparanase[5] Mmp2[6,7,8] and uPA[9]. Genome wide analyses of DNA methylation changes in promoters in liver cancer [10] revealed that a significant fraction of promoters were hypomethylated. The adverse effects that SAM might have on normal cell epigenetic programs have not been thoroughly investigated
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