S-adenosylmethionine and methylthioadenosine inhibit cancer metastasis by targeting MicroRNA 34a/b-methionine adenosyltransferase 2A/2B axis
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Maria Lauda Tomasi1,*, Carla Cossu1,2,*, Ylenia Spissu1,2, Andrea Floris1,3, Minjung Ryoo1, Ainhoa Iglesias-Ara4, Qiang Wang1, Stephen J. Pandol1,7, Neil A. Bhowmick5,6,8, Ekihiro Seki1,5,8, Edwin M. Posadas6,7 and Shelly C. Lu1,7
1Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
2Department of Medicine, University of Sassari, Sassari, Italy
3Department of Biomedical Science, University of Cagliari, Cagliari, Italy
4Department of Genetics, Faculty of Science and Technology, University of The Basque Country, Bilbao, Spain
5Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
6Urologic Oncology Program, Division of Hematology & Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
7Translational Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
8Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
Shelly C. Lu, email: [email protected]
Keywords: S-adenosylmethionine, methylthioadenosine, miR-34 family, methionine adenosyltransferase genes, cancer metastasis
Received: June 17, 2017 Accepted: July 16, 2017 Published: August 12, 2017
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.
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