The bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Chiara Pastori, Philipp Kapranov, Clara Penas, Veronica Peschansky, Claude Henry Volmar, Jann N. Sarkaria, Amade Bregy, Ricardo J Komotar, Georges St Laurent, Nagi Ayad, Claes R Wahlestedt, Thomas C. Roberts

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumorpromoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.

Original languageEnglish (US)
Pages (from-to)8326-8331
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number27
DOIs
StatePublished - Jul 7 2015

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Long Noncoding RNA
Antisense RNA
Glioblastoma
Proteins
Epigenomics
Neoplasms
Chromatin Immunoprecipitation
Growth
Oncogenes
Clinical Trials

Keywords

  • BRD4
  • Epigenetics
  • Glioblastoma
  • I-BET151
  • Long noncoding RNAs

ASJC Scopus subject areas

  • General

Cite this

The bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. / Pastori, Chiara; Kapranov, Philipp; Penas, Clara; Peschansky, Veronica; Volmar, Claude Henry; Sarkaria, Jann N.; Bregy, Amade; Komotar, Ricardo J; Laurent, Georges St; Ayad, Nagi; Wahlestedt, Claes R; Roberts, Thomas C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 27, 07.07.2015, p. 8326-8331.

Research output: Contribution to journalArticle

Pastori, Chiara ; Kapranov, Philipp ; Penas, Clara ; Peschansky, Veronica ; Volmar, Claude Henry ; Sarkaria, Jann N. ; Bregy, Amade ; Komotar, Ricardo J ; Laurent, Georges St ; Ayad, Nagi ; Wahlestedt, Claes R ; Roberts, Thomas C. / The bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 27. pp. 8326-8331.
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AU - Pastori, Chiara

AU - Kapranov, Philipp

AU - Penas, Clara

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AU - Volmar, Claude Henry

AU - Sarkaria, Jann N.

AU - Bregy, Amade

AU - Komotar, Ricardo J

AU - Laurent, Georges St

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AB - Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumorpromoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.

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