A novel role of secreted methionine adenosyltransferase α2 in colorectal liver metastases.

BACKGROUND: Colorectal liver metastasis (CRLM) occurs frequently in patients with colorectal cancer (CRC). Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine, the principal methyl donor. MAT1A (encodes MATα1) is expressed mainly in normal adult liver, whereas MAT2A (encodes MATα2) is expressed in all extrahepatic tissues. MAT1A is a major defense against CRLM as loss of Mat1a sensitizes the liver to CRLM. In contrast, MAT2A is overexpressed in CRC and promotes oncogenicity. Here, we sought to determine if CRCs secrete MATα2 and if this influences CRLM. METHODS: Our study included human hepatocytes, human CRC cells, extracellular vesicle (EV) isolation, chromatin immunoprecipitation (ChIP), ChIP-seq, promoter activity assays, proliferation, migration, and invasion assays, western blotting, immunohistochemistry and immunofluorescence. We confirmed some of the findings using human hepatocyte spheroids, CRLM and normal liver tissue array, and plasma samples. RESULTS: CRCs secrete MATα2 in free but truncated form (MATα2-t) and intact within EVs (EV-MATα2). EV-MATα2 can be internalized by human hepatocytes and CRCs, found within the nucleus, which then binds to MAT1A and MAT2A promoters on ChIP to lower and increase MAT1A and MAT2A promoter activities, respectively. In human CRLM samples, hepatocytes in nontumor regions express lower MATα1 but higher MATα2 as compared to normal liver. Treating RKO cells with EVs released from RKO cells overexpressing MAT2A promoted cell proliferation, migration, and invasion. MATα2-t was detected at a higher level in media from colon, pancreatic, and prostate cancer cell lines than corresponding normal epithelial cells as well as in the plasma of CRC patients as compared to healthy controls. RKO cells treated with MATα2-t activated focal adhesion kinase (FAK), an important kinase for cancer cell evasion of apoptosis. Conversely, treatment with MATα2 neutralizing antibody inhibited FAK and induced apoptosis. CONCLUSIONS: CRC cells secrete both MATα2 within EVs and free MATα2-t. EV-MATα2 can be internalized and act as a transcription factor to lower hepatocytes' MAT1A, the major defense against CRLM, while promoting CRC oncogenicity. Freely released MATα2-t acts as a ligand in an autocrine fashion to activate FAK, which is essential for CRC survival. Taken together, secreted MATα2 plays an essential role in promoting CRLM.