The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis

Abstract High-grade serous ovarian carcinoma (HGSOC) is the most aggressive type of ovarian cancer, often diagnosed at advanced stages. Molecularly, HGSOC shows high degree of genomic instability associated with large number of genetic alterations. BRD4 is the 4th most amplified gene in HGSOC, which...

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Autores principales:	Ana Luiza Drumond-Bock, Magdalena Bieniasz
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	BRD4 High-grade serous ovarian carcinoma Gene amplification BET inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/6c7535b1b6594f3bb5a8810ca124ef10
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spelling	oai:doaj.org-article:6c7535b1b6594f3bb5a8810ca124ef102021-11-14T12:05:36ZThe role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis10.1186/s12943-021-01424-51476-4598https://doaj.org/article/6c7535b1b6594f3bb5a8810ca124ef102021-11-01T00:00:00Zhttps://doi.org/10.1186/s12943-021-01424-5https://doaj.org/toc/1476-4598Abstract High-grade serous ovarian carcinoma (HGSOC) is the most aggressive type of ovarian cancer, often diagnosed at advanced stages. Molecularly, HGSOC shows high degree of genomic instability associated with large number of genetic alterations. BRD4 is the 4th most amplified gene in HGSOC, which correlates with poor patients’ prognosis. BRD4 is constitutively expressed and generates two proteins, BRD4 long (BRD4-L) and BRD4 short (BRD4-S). Both isoforms contain bromodomains that bind to lysine-acetylated histones. Amongst other functions, BRD4 participates in chromatin organization, acetylation of histones, transcriptional control and DNA damage repair. In cancer patients with amplified BRD4, the increased activity of BRD4 is associated with higher expression of oncogenes, such as MYC, NOTCH3 and NRG1. BRD4-driven oncogenes promote increased tumor cells proliferation, genetic instability, epithelial-mesenchymal transition, metastasis and chemoresistance. Ablation of BRD4 activity can be successfully achieved with bromodomain inhibitors (BETi) and degraders, and it has been applied in pre-clinical and clinical settings. Inhibition of BRD4 function has an effective anti-cancer effect, reducing tumor growth whether ablated by single agents or in combination with other drugs. When combined with standard chemotherapy, BETi are capable of sensitizing highly resistant ovarian cancer cell lines to platinum drugs. Despite the evidence that BRD4 amplification in ovarian cancer contributes to poor patient prognosis, little is known about the specific mechanisms by which BRD4 drives tumor progression. In addition, newly emerging data revealed that BRD4 isoforms exhibit contradicting functions in cancer. Therefore, it is paramount to expand studies elucidating distinct roles of BRD4-L and BRD4-S in HGSOC, which has important implications on development of therapeutic approaches targeting BRD4.Ana Luiza Drumond-BockMagdalena BieniaszBMCarticleBRD4High-grade serous ovarian carcinomaGene amplificationBET inhibitorsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Cancer, Vol 20, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	BRD4 High-grade serous ovarian carcinoma Gene amplification BET inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	BRD4 High-grade serous ovarian carcinoma Gene amplification BET inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ana Luiza Drumond-Bock Magdalena Bieniasz The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis
description	Abstract High-grade serous ovarian carcinoma (HGSOC) is the most aggressive type of ovarian cancer, often diagnosed at advanced stages. Molecularly, HGSOC shows high degree of genomic instability associated with large number of genetic alterations. BRD4 is the 4th most amplified gene in HGSOC, which correlates with poor patients’ prognosis. BRD4 is constitutively expressed and generates two proteins, BRD4 long (BRD4-L) and BRD4 short (BRD4-S). Both isoforms contain bromodomains that bind to lysine-acetylated histones. Amongst other functions, BRD4 participates in chromatin organization, acetylation of histones, transcriptional control and DNA damage repair. In cancer patients with amplified BRD4, the increased activity of BRD4 is associated with higher expression of oncogenes, such as MYC, NOTCH3 and NRG1. BRD4-driven oncogenes promote increased tumor cells proliferation, genetic instability, epithelial-mesenchymal transition, metastasis and chemoresistance. Ablation of BRD4 activity can be successfully achieved with bromodomain inhibitors (BETi) and degraders, and it has been applied in pre-clinical and clinical settings. Inhibition of BRD4 function has an effective anti-cancer effect, reducing tumor growth whether ablated by single agents or in combination with other drugs. When combined with standard chemotherapy, BETi are capable of sensitizing highly resistant ovarian cancer cell lines to platinum drugs. Despite the evidence that BRD4 amplification in ovarian cancer contributes to poor patient prognosis, little is known about the specific mechanisms by which BRD4 drives tumor progression. In addition, newly emerging data revealed that BRD4 isoforms exhibit contradicting functions in cancer. Therefore, it is paramount to expand studies elucidating distinct roles of BRD4-L and BRD4-S in HGSOC, which has important implications on development of therapeutic approaches targeting BRD4.
format	article
author	Ana Luiza Drumond-Bock Magdalena Bieniasz
author_facet	Ana Luiza Drumond-Bock Magdalena Bieniasz
author_sort	Ana Luiza Drumond-Bock
title	The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis
title_short	The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis
title_full	The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis
title_fullStr	The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis
title_full_unstemmed	The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis
title_sort	role of distinct brd4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis
publisher	BMC
publishDate	2021
url	https://doaj.org/article/6c7535b1b6594f3bb5a8810ca124ef10
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The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis

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