S-adenosylmethionine and methylthioadenosine inhibit cancer metastasis by targeting microRNA 34a/b-methionine adenosyltransferase 2A/2B axis

Abstract

MicroRNA-34a (miR-34a) is down-regulated in colorectal cancers (CRC) and required for interleukin-6 (IL-6)-induced CRC metastasis. Mice lacking miR-34a developed more invasive cancer in a colitis-associated cancer model. In the same model, S-adenosylmethionine (SAMe) and methylthioadenosine (MTA) inhibited IL-6/STAT3 and lowered tumor burden. SAMe and MTA reduce the expression of methionine adenosyltransferase 2A (MAT2A) and there are consensus binding sites for miR-34a/b in the MAT2A 3’UTR. Here we examined whether SAMe/MTA influence miR-34a/b expression and cancer metastasis. We found SAMe and MTA raised miR-34a/b expression in CRC cell lines, inhibited migration and invasion in vitro and liver metastasis in vivo. Like CRC, MAT2A and MAT2B expression is induced in human pancreas and prostate cancers. Treatment with SAMe, MTA, miR-34a or miR-34b inhibited MAT2A expression mainly at the protein level. MAT2B protein level also fell because MAT2A and MAT2B enhance each other’s protein stability. Overexpressing miR-34a or miR-34b inhibited while MAT2A or MAT2B enhanced CRC migration and invasion. Co-expressing either miR-34a/b had minimal to no effect on MAT2A/MAT2B’s ability to increase migration, invasion and growth. Taken together, MAT2A and MAT2B are important targets of miR-34a/b and SAMe and MTA target this axis, suppressing MAT2A/MAT2B while raising miR-34a/b expression, inhibiting cancer metastasis.

5'-Methylthioadenosine and Cancer: old molecules, new understanding

“…In a chemically induced hepatocarcinogenesis rat model, both endogenous and exogenous MTA levels were found to be negatively correlated with preneoplastic liver lesions and DNA synthesis 27, 29. Similar inhibitory effects of MTA have also been observed in cultured HCT116 human colon cancer cells, colorectal cancer cells, HeLa cervical cancer cells, Daudi and Raji lymphoma cells, erythroleukemia cells, promyelocytic cells and mitogen stimulated human peripheral blood lymphocytes 8, 31-35.…”

“…It is noteworthy that most of these studies indicate that MTA had the opposite effect on the apoptosis of normal versus cancerous cells. In vitro , it enhances the apoptosis of human RKO and SW620 colon cancer cells 35, 41 and of HuH7 liver cancer cells 42. However, it does not have such effects on normal colon epithelial cells or even has anti-apoptotic effects on normal hepatocytes 41, 42.…”

A novel mechanism of the M1‐M2 methionine adenosyltransferase switch‐mediated hepatocellular carcinoma metastasis

“…These discrepancies might be due to the different cellular context and tumor types and remain to be elucidated. Interestingly, while this article was in preparation, Tomasi et al reported that overexpression of MAT2A promoted ERK activation and cell migration in prostate and pancreatic cancer cells which do not express MAT1A. Taken our and Tomasi's data together, it is suggested that the liver‐specific MAT1A may play a critical role in metastasis of liver cancer and both increasing MAT2A and decreasing MAT1A are necessary for HCC metastasis.…”

The biological functions of target genes in pan-cancers and cell lines were predicted by miR-375 microarray data from GEO database and bioinformatics

“…Over-expression of miR-34a or miR-34b lead to the low expression level of MAT2B, mainly in the protein expression level of CWR22Rv-1 and MIA PaCa-2 cells [ 65 ]. Using microRNA microarray, Lo TF et al [ 66 ] found that after berberine treatment, the expression of miR-21-3p (previously named miR-21) up-regulated in HepG2 human hepatoma cell line.…”