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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 languageEnglish
Pages (from-to)1328-1340
Number of pages13
JournalCell Death and Differentiation
Volume22
Issue number8
DOIs
Publication statusPublished - Aug 7 2015

Fingerprint

MicroRNAs
Cisplatin
Lung Neoplasms
Epigenomics
Growth
DNA Methylation
Neoplasms
Histones
trichostatin A
Exosomes
Deoxycytidine
Messenger RNA
Cell Movement
Cell Proliferation
Apoptosis
Therapeutics

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Adi Harel, S., Bossel Ben-Moshe, N., Aylon, Y., Bublik, D. R., Moskovits, N., Toperoff, G., ... Oren, M. (2015). Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth. Cell Death and Differentiation, 22(8), 1328-1340. https://doi.org/10.1038/cdd.2014.221

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth. / Adi Harel, S.; Bossel Ben-Moshe, N.; Aylon, Y.; Bublik, D. R.; Moskovits, N.; Toperoff, G.; Azaiza, D.; Biagoni, F.; Fuchs, G.; Wilder, S.; Hellman, A.; Blandino, G.; Domany, E.; Oren, M.

In: Cell Death and Differentiation, Vol. 22, No. 8, 07.08.2015, p. 1328-1340.

Research output: Contribution to journalArticle

Adi Harel, S, Bossel Ben-Moshe, N, Aylon, Y, Bublik, DR, Moskovits, N, Toperoff, G, Azaiza, D, Biagoni, F, Fuchs, G, Wilder, S, Hellman, A, Blandino, G, Domany, E & Oren, M 2015, 'Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth', Cell Death and Differentiation, vol. 22, no. 8, pp. 1328-1340. https://doi.org/10.1038/cdd.2014.221
Adi Harel, S. ; Bossel Ben-Moshe, N. ; Aylon, Y. ; Bublik, D. R. ; Moskovits, N. ; Toperoff, G. ; Azaiza, D. ; Biagoni, F. ; Fuchs, G. ; Wilder, S. ; Hellman, A. ; Blandino, G. ; Domany, E. ; Oren, M. / Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 8. pp. 1328-1340.
@article{f60a6320233d4a5d8505cb305eb72351,
title = "Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth",
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.",
author = "{Adi Harel}, S. and {Bossel Ben-Moshe}, N. and Y. Aylon and Bublik, {D. R.} and N. Moskovits and G. Toperoff and D. Azaiza and F. Biagoni and G. Fuchs and S. Wilder and A. Hellman and G. Blandino and E. Domany and M. Oren",
year = "2015",
month = "8",
day = "7",
doi = "10.1038/cdd.2014.221",
language = "English",
volume = "22",
pages = "1328--1340",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "8",

}

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.

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

UR - http://www.scopus.com/inward/citedby.url?scp=84935746201&partnerID=8YFLogxK

U2 - 10.1038/cdd.2014.221

DO - 10.1038/cdd.2014.221

M3 - Article

AN - SCOPUS:84935746201

VL - 22

SP - 1328

EP - 1340

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 8

ER -