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

Dipanwita Das, Jia Yu Leung, Vinay Tergaonkar

    Biorxiv : the Preprint Server for Biology
    |August 7, 2023
    PubMed

    Insights

    Bromodomain and extraterminal (BET) protein BRD4 has two isoforms, BRD4-L and BRD4-S, with distinct roles in embryonal rhabdomyosarcoma. BRD4-L drives tumor growth, while BRD4-S restrains metastasis.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cancer Genetics

    Background:

    • Bromodomain and extraterminal (BET) protein BRD4 is deregulated in various cancers, making it a key drug target.
    • Understanding the distinct functions of BRD4's long (BRD4-L) and short (BRD4-S) isoforms is crucial for effective cancer therapy.
    • The parallel analysis of BRD4-L and BRD4-S functions is limited in most cancers, hindering the development of targeted therapies.

    Approach:

    • Functional assays and transcriptomic analysis were employed to investigate the roles of BRD4-L and BRD4-S.
    • In vivo studies were conducted to assess the impact of BRD4-L and BRD4-S depletion on tumor progression and metastasis.
    • Investigated the molecular mechanisms by which BRD4 isoforms regulate gene expression, including their interaction with RNA Polymerase II and specific gene promoters.

    Key Points:

    • BRD4-L exhibits an oncogenic role in embryonal rhabdomyosarcoma, inhibiting myogenic differentiation partly via myostatin activation.
    • BRD4-L depletion impairs tumor progression but does not affect metastasis.
    • BRD4-S depletion does not significantly impact tumor growth but promotes metastasis by activating integrin gene promoters through BRD4-L enrichment.

    Conclusions:

    • BRD4 isoforms, BRD4-L and BRD4-S, possess distinct and opposing functions in embryonal rhabdomyosarcoma.
    • BRD4-S acts as a tumor suppressor by limiting the oncogenic potential of BRD4-L and restraining metastasis.
    • Targeting BRD4 isoform-specific functions offers a promising strategy for cancer treatment.

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