BRD4 inhibitors block telomere elongation

Steven Wang, Alexandra M. Pike, Stella S. Lee, Margaret A. Strong, Carla J. Connelly, Carol W Greider

Research output: Contribution to journalArticle

Abstract

Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.

Original languageEnglish (US)
Pages (from-to)8403-8410
Number of pages8
JournalNucleic Acids Research
Volume45
Issue number14
DOIs
StatePublished - Aug 21 2017

Fingerprint

Telomere
Proteins
Telomerase
Maintenance
Telomere Shortening
Neoplasms
Small Interfering RNA
DNA Damage
Phosphotransferases
Clinical Trials
Apoptosis

ASJC Scopus subject areas

  • Genetics

Cite this

Wang, S., Pike, A. M., Lee, S. S., Strong, M. A., Connelly, C. J., & Greider, C. W. (2017). BRD4 inhibitors block telomere elongation. Nucleic Acids Research, 45(14), 8403-8410. https://doi.org/10.1093/nar/gkx561

BRD4 inhibitors block telomere elongation. / Wang, Steven; Pike, Alexandra M.; Lee, Stella S.; Strong, Margaret A.; Connelly, Carla J.; Greider, Carol W.

In: Nucleic Acids Research, Vol. 45, No. 14, 21.08.2017, p. 8403-8410.

Research output: Contribution to journalArticle

Wang, S, Pike, AM, Lee, SS, Strong, MA, Connelly, CJ & Greider, CW 2017, 'BRD4 inhibitors block telomere elongation', Nucleic Acids Research, vol. 45, no. 14, pp. 8403-8410. https://doi.org/10.1093/nar/gkx561
Wang S, Pike AM, Lee SS, Strong MA, Connelly CJ, Greider CW. BRD4 inhibitors block telomere elongation. Nucleic Acids Research. 2017 Aug 21;45(14):8403-8410. https://doi.org/10.1093/nar/gkx561
Wang, Steven ; Pike, Alexandra M. ; Lee, Stella S. ; Strong, Margaret A. ; Connelly, Carla J. ; Greider, Carol W. / BRD4 inhibitors block telomere elongation. In: Nucleic Acids Research. 2017 ; Vol. 45, No. 14. pp. 8403-8410.
@article{5b597ff5cb4d4ac09315de6daf33e9aa,
title = "BRD4 inhibitors block telomere elongation",
abstract = "Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.",
author = "Steven Wang and Pike, {Alexandra M.} and Lee, {Stella S.} and Strong, {Margaret A.} and Connelly, {Carla J.} and Greider, {Carol W}",
year = "2017",
month = "8",
day = "21",
doi = "10.1093/nar/gkx561",
language = "English (US)",
volume = "45",
pages = "8403--8410",
journal = "Nucleic Acids Research",
issn = "1362-4962",
publisher = "Oxford University Press",
number = "14",

}

TY - JOUR

T1 - BRD4 inhibitors block telomere elongation

AU - Wang, Steven

AU - Pike, Alexandra M.

AU - Lee, Stella S.

AU - Strong, Margaret A.

AU - Connelly, Carla J.

AU - Greider, Carol W

PY - 2017/8/21

Y1 - 2017/8/21

N2 - Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.

AB - Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.

UR - http://www.scopus.com/inward/record.url?scp=85031856314&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031856314&partnerID=8YFLogxK

U2 - 10.1093/nar/gkx561

DO - 10.1093/nar/gkx561

M3 - Article

C2 - 28854735

AN - SCOPUS:85031856314

VL - 45

SP - 8403

EP - 8410

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 1362-4962

IS - 14

ER -