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

// Maria Lauda Tomasi 1, * , Carla Cossu 1, 2, * , Ylenia Spissu 1, 2 , Andrea Floris 1, 3 , Minjung Ryoo 1 , Ainhoa Iglesias-Ara 4 , Qiang Wang 1 , Stephen J. Pandol 1, 7 , Neil A. Bhowmick 5, 6, 8 , Ekihiro Seki 1, 5, 8 , Edwin M. Posadas 6, 7 and Shelly C. Lu 1, 7 1 Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA 2 Department of Medicine, University of Sassari, Sassari, Italy 3 Department of Biomedical Science, University of Cagliari, Cagliari, Italy 4 Department of Genetics, Faculty of Science and Technology, University of The Basque Country, Bilbao, Spain 5 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA 6 Urologic Oncology Program, Division of Hematology & Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA 7 Translational Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA 8 Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA * Shared first-authorship Correspondence to: Shelly C. Lu, email: shelly.lu@cshs.org Keywords: S-adenosylmethionine, methylthioadenosine, miR-34 family, methionine adenosyltransferase genes, cancer metastasis Received: June 17, 2017 Accepted: July 16, 2017 Published: August 12, 2017 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.