TY - JOUR
T1 - Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth
AU - Adi Harel, S.
AU - Bossel Ben-Moshe, N.
AU - Aylon, Y.
AU - Bublik, D. R.
AU - Moskovits, N.
AU - Toperoff, G.
AU - Azaiza, D.
AU - Biagoni, F.
AU - Fuchs, G.
AU - Wilder, S.
AU - Hellman, A.
AU - Blandino, G.
AU - Domany, E.
AU - Oren, M.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/8/7
Y1 - 2015/8/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84935746201&partnerID=8YFLogxK
U2 - 10.1038/cdd.2014.221
DO - 10.1038/cdd.2014.221
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C2 - 25591738
AN - SCOPUS:84935746201
SN - 1350-9047
VL - 22
SP - 1328
EP - 1340
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 8
ER -
