BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors

Garrett W. Rhyasen; Yi Yao; Jingwen Zhang; Austin Dulak; Lillian Castriotta; Kelly Jacques; Wei Zhao; Farzin Gharahdaghi; Maureen M. Hattersley; Paul D. Lyne; Edwin Clark; Michael Zinda; Stephen E. Fawell; Gordon B. Mills; Huawei Chen

doi:10.1371/journal.pone.0200826

BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors

Garrett W. Rhyasen, Yi Yao, Jingwen Zhang, Austin Dulak, Lillian Castriotta, Kelly Jacques, Wei Zhao, Farzin Gharahdaghi, Maureen M. Hattersley, Paul D. Lyne, Edwin Clark, Michael Zinda, Stephen E. Fawell, Gordon B. Mills, Huawei Chen

Research output: Contribution to journal › Article

7 Scopus citations

Abstract

BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes to acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent BRD4 gene amplifications. Despite previously described cancer dependencies, it is unclear whether BRD4 amplification events are oncogenic in HGSOC. We find that physiologically relevant levels of expression of BRD4 isoforms in non-transformed ovarian cells result in cellular transformation. Transcriptional profiling of BRD4-trans-formed ovarian cells, and BRD4-amplified HGSOC patient samples revealed shared expression patterns, including enriched MYC, and E2F1 gene signatures. Furthermore, we demonstrate that a novel BET inhibitor, AZD5153, is highly active in BRD4-amplified patient derived xenografts and uncover Neuregulin-1 as a novel BRD4 effector. Experiments involving Neuregulin-1 inhibition and exogenous addition, demonstrate Neuregulin-1 as necessary and sufficient for BRD4-mediated transformation. This study demonstrates the oncogenic potential of BRD4 amplification in cancer and establishes BRD4-amplified HGSOC as a potential patient population that could benefit from BET inhibitors.

Original language	English (US)
Article number	e0200826
Journal	PloS one
Volume	13
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0200826
State	Published - Jul 2018

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
General

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Rhyasen, G. W., Yao, Y., Zhang, J., Dulak, A., Castriotta, L., Jacques, K., Zhao, W., Gharahdaghi, F., Hattersley, M. M., Lyne, P. D., Clark, E., Zinda, M., Fawell, S. E., Mills, G. B., & Chen, H. (2018). BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors. PloS one, 13(7), [e0200826]. https://doi.org/10.1371/journal.pone.0200826

BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors. / Rhyasen, Garrett W.; Yao, Yi; Zhang, Jingwen; Dulak, Austin; Castriotta, Lillian; Jacques, Kelly; Zhao, Wei; Gharahdaghi, Farzin; Hattersley, Maureen M.; Lyne, Paul D.; Clark, Edwin; Zinda, Michael; Fawell, Stephen E.; Mills, Gordon B.; Chen, Huawei.

In: PloS one, Vol. 13, No. 7, e0200826, 07.2018.

Research output: Contribution to journal › Article

Rhyasen, GW, Yao, Y, Zhang, J, Dulak, A, Castriotta, L, Jacques, K, Zhao, W, Gharahdaghi, F, Hattersley, MM, Lyne, PD, Clark, E, Zinda, M, Fawell, SE, Mills, GB & Chen, H 2018, 'BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors', PloS one, vol. 13, no. 7, e0200826. https://doi.org/10.1371/journal.pone.0200826

Rhyasen, Garrett W. ; Yao, Yi ; Zhang, Jingwen ; Dulak, Austin ; Castriotta, Lillian ; Jacques, Kelly ; Zhao, Wei ; Gharahdaghi, Farzin ; Hattersley, Maureen M. ; Lyne, Paul D. ; Clark, Edwin ; Zinda, Michael ; Fawell, Stephen E. ; Mills, Gordon B. ; Chen, Huawei. / BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors. In: PloS one. 2018 ; Vol. 13, No. 7.

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abstract = "BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes to acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent BRD4 gene amplifications. Despite previously described cancer dependencies, it is unclear whether BRD4 amplification events are oncogenic in HGSOC. We find that physiologically relevant levels of expression of BRD4 isoforms in non-transformed ovarian cells result in cellular transformation. Transcriptional profiling of BRD4-trans-formed ovarian cells, and BRD4-amplified HGSOC patient samples revealed shared expression patterns, including enriched MYC, and E2F1 gene signatures. Furthermore, we demonstrate that a novel BET inhibitor, AZD5153, is highly active in BRD4-amplified patient derived xenografts and uncover Neuregulin-1 as a novel BRD4 effector. Experiments involving Neuregulin-1 inhibition and exogenous addition, demonstrate Neuregulin-1 as necessary and sufficient for BRD4-mediated transformation. This study demonstrates the oncogenic potential of BRD4 amplification in cancer and establishes BRD4-amplified HGSOC as a potential patient population that could benefit from BET inhibitors.",

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