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

doi:10.1038/cdd.2014.221

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 journal › Article › peer-review

66 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 language	American English
Pages (from-to)	1328-1340
Number of pages	13
Journal	Cell Death and Differentiation
Volume	22
Issue number	8
DOIs	https://doi.org/10.1038/cdd.2014.221
State	Published - 7 Aug 2015
Externally published	Yes

Bibliographical note

Funding 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.

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/cdd.2014.221

Cite this

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. (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

@article{c2b10433201344329d0462baff9acae3,

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",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = aug,

day = "7",

doi = "10.1038/cdd.2014.221",

language = "American English",

volume = "22",

pages = "1328--1340",

journal = "Cell Death and Differentiation",

issn = "1350-9047",

publisher = "Nature Publishing Group",

number = "8",

}

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

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 - Funding 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. 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

M3 - Article

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 -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this