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bioRxiv · 10.1101/2023.07.26.550665

BRD4 isoforms have distinct roles in tumor progression and metastasis in embryonal rhabdomyosarcoma

Taneja, R.·Das, D.·Leung, J. Y.·Tergaonkar, V.·Loh, A. H. P.·Chiang, C.-M.
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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 analyzed 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 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 tumor progression but does not impact metastasis. On the other hand, depletion of BRD4-S has no significant impact on tumor 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. Our work unveils isoform-specific functions of BRD4 and demonstrates that BRD4-S functions as a gatekeeper to constrain the full oncogenic potential of BRD4-L.

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Taneja, R., Das, D., Leung, J. Y., Tergaonkar, V., Loh, A. H. P., Chiang, C.-M.. 2023-07-27. BRD4 isoforms have distinct roles in tumor progression and metastasis in embryonal rhabdomyosarcoma. https://doi.org/10.1101/2023.07.26.550665

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