Opposing Functions of BRD4 Isoforms in Breast Cancer

Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and e...

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Published in:Molecular cell 2020-06, Vol.78 (6), p.1114-1132.e10
Main Authors: Wu, Shwu-Yuan, Lee, Chien-Fei, Lai, Hsien-Tsung, Yu, Cheng-Tai, Lee, Ji-Eun, Zuo, Hao, Tsai, Sophia Y., Tsai, Ming-Jer, Ge, Kai, Wan, Yihong, Chiang, Cheng-Ming
Format: Article
Language:English
Subjects:
Animals
BET inhibitor
BRD4
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
bromodomain
Cell Cycle Proteins - metabolism
Cell Cycle Proteins - physiology
Cell Line, Tumor
Cell Movement
Cell Proliferation
CUT&RUN
drug resistance
ECM
enhancer
epigenetics
Female
Gene Expression Regulation, Neoplastic - genetics
Genes, Homeobox
Homeodomain Proteins - metabolism
Humans
Mice
Neoplasm Invasiveness
Nuclear Proteins - metabolism
Protein Isoforms - metabolism
Proteins - antagonists & inhibitors
Proteins - metabolism
TNBC
transcription factor
Transcription Factors - metabolism
Transcription Factors - physiology
Transcription, Genetic - genetics
Triple Negative Breast Neoplasms - genetics
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Summary:Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4. [Display omitted] •Oncogenic BRD4-S and tumor-suppressive BRD4-L in breast cancer•Inducible BRD4-L/S transgenic mice exhibiting opposing functions of BRD4 isoforms•Genome-wide RNA-seq, ChIP-seq, and CUT&RUN profiling of BRD4-S and BRD4-L•EN1/BRD4-S-coregulated enhancer modulating the matrisome ECM network With BRD4 isoform-specific antibodies and knockdown and mouse xenograft and transgene expression, Wu et al. demonstrate oncogenic BRD4-S and tumor-suppressive BRD4-L have opposing functions in breast cancer initiation and development, partly through enhancer regulation of matrisome extracellular network modulating cancer cell migration and metastasis.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2020.04.034