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Title: BRD4 isoforms have distinct roles in tumour progression and metastasis in rhabdomyosarcoma.
Authors: Das, Dipanwita 
Leung, Jia Yu
Balamurugan, Shivaranjani 
Tergaonkar, Vinay 
Loh, Amos Hong Pheng 
Chiang, Cheng-Ming
Taneja, Reshma 
Keywords: Differentiation
Issue Date: 8-Jan-2024
Publisher: Springer Science and Business Media LLC
Citation: Das, Dipanwita, Leung, Jia Yu, Balamurugan, Shivaranjani, Tergaonkar, Vinay, Loh, Amos Hong Pheng, Chiang, Cheng-Ming, Taneja, Reshma (2024-01-08). BRD4 isoforms have distinct roles in tumour progression and metastasis in rhabdomyosarcoma.. EMBO Rep. ScholarBank@NUS Repository.
Abstract: BRD4, a bromodomain and extraterminal (BET) protein, is deregulated in multiple cancers and has emerged as a promising drug target. However, the function of the two main BRD4 isoforms (BRD4-L and BRD4-S) has not been analysed in parallel in most cancers. This complicates determining therapeutic efficacy of pan-BET inhibitors. In this study, using functional and transcriptomic analysis, we show that BRD-L and BRD4-S isoforms play distinct roles in fusion negative embryonal rhabdomyosarcoma. BRD4-L has an oncogenic role and inhibits myogenic differentiation, at least in part, by activating myostatin expression. Depletion of BRD4-L in vivo impairs tumour progression but does not impact metastasis. On the other hand, depletion of BRD4-S has no significant impact on tumour growth, but strikingly promotes metastasis in vivo. Interestingly, BRD4-S loss results in the enrichment of BRD4-L and RNA Polymerase II at integrin gene promoters resulting in their activation. In fusion positive alveolar rhabdomyosarcoma, BRD4-L is unrestricted in its oncogenic role, with no evident involvement of BRD4-S. Our work unveils isoform-specific functions of BRD4 in rhabdomyosarcoma.
Source Title: EMBO Rep
ISSN: 1469-221X
DOI: 10.1038/s44319-023-00033-1
Appears in Collections:Staff Publications

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Post-print Available on 07-07-2024

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