4.7 Article

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

Journal

CELL DEATH AND DIFFERENTIATION
Volume 22, Issue 8, Pages 1328-1340

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2014.221

Keywords

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Funding

  1. Dr Miriam and Sheldon Adelson Medical Research Foundation
  2. EC [201102]
  3. Center of Excellence grant from Flight Attendant Medical Research Institute (FAMRI)
  4. Robert Bosch Foundation [11.5.8000.0094.0]
  5. Leir Charitable Foundation
  6. M.D. Moross Institute for Cancer Research
  7. McGill-Weizmann Collaboration Program

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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.

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