MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumor-suppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such 'epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy.
Bibliographical noteFunding Information:
Acknowledgements. We thank V. Gorgoulis for the kind gift of immortalized HBECs. This work was supported in part by the Dr Miriam and Sheldon Adelson Medical Research Foundation, EC FP7 grant 201102 (ONCOMIRS), a Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI), the Robert Bosch Foundation (project 11.5.8000.0094.0), the Leir Charitable Foundation, The M.D. Moross Institute for Cancer Research and the McGill-Weizmann Collaboration Program. ED is incumbent of the Henry J. Leir Professorial Chair. MO is incumbent of the Andre Lwoff chair in Molecular Biology.
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