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

S. Adi Harel, N. Bossel Ben-Moshe, Y. Aylon, D. R. Bublik, N. Moskovits, G. Toperoff, D. Azaiza, F. Biagoni, G. Fuchs, S. Wilder, A. Hellman, G. Blandino, E. Domany, M. Oren*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1328-1340
Number of pages13
JournalCell Death and Differentiation
Volume22
Issue number8
DOIs
StatePublished - 7 Aug 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

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