BRD4 and Cancer: going beyond transcriptional regulation

Abstract

BRD4, member of the Bromodomain and Extraterminal (BET) protein family, is largely acknowledged in cancer for its role in super-enhancers (SEs) organization and oncogenes expression regulation. Inhibition of BRD4 shortcuts the communication between SEs and target promoters with a subsequent cell-specific repression of oncogenes to which cancer cells are addicted and cell death. To date, this is the most credited mechanism of action of BET inhibitors, a class of small molecules targeting BET proteins which are currently in clinical trials in several cancer settings.However, recent evidence indicates that BRD4 relevance in cancer goes beyond its role in transcription regulation and identifies this protein as a keeper of genome stability.Indeed, a non-transcriptional role of BRD4 in controlling DNA damage checkpoint activation and repair as well as telomere maintenance has been proposed, throwing new lights into the multiple functions of this protein and opening new perspectives on the use of BETi in cancer. Here we discuss the current available information on non-canonical, non-transcriptional functions of BRD4 and on their implications in cancer biology. Integrating this information with the already known BRD4 role in gene expression regulation, we propose a “common” model to explain BRD4 genomic function. Furthermore, in light of the transversal function of BRD4, we provide new interpretation for the cytotoxic activity of BETi and we discuss new possibilities for a wide and focused employment of these drugs in clinical settings.

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

“…The BET (bromodomain and extraterminal domain) family of proteins consists of BRD2, BRD3, BRD4 and BRDT, and the bromodomain structure comprises four alpha helices separated by variable loop regions, which can recognize acetylation sites and recruit transcription factors . Based on its strong effect on transcriptional regulation, the role of the BET family in the promotion of the biological behaviour of cancer cells has been identified . Furthermore, the BRD4 inhibitor (+)‐JQ1 (JQ1) has been shown to suppress the proliferation of cancer cells, indicating that JQ1 may be a new therapeutic agent for cancer treatment .…”

“…BRD4 was shown to regulate PTEN and the PI3K/AKT pathway . The important roles of BRD4 in transcriptional activation and the initiation of tumour formation have led to the consideration of selective inhibition of BRD4 as a promising therapeutic strategy against cancer . The amino‐terminal bromodomains of BRD4 have been targeted using several selective small‐molecule inhibitors, such as I‐BET762 and JQ1, and promising antiproliferative effects have been observed along with promising clinical significance in a range of cancers .…”

Jumonji domain‐containing protein 6 protein and its role in cancer

“…Brd4 binds to acetylated lysine residues on histone tails and other nuclear proteins through bromodomains which have modest affinity for acetylated lysine in a range of polypeptide contexts, and recruits transcriptional regulators such as positive transcription elongation factor b (P‐TEFb) via CTD (carboxyl‐terminal domain) and mediator complex to influence gene expression . Cancer‐associated genes seem to be selectively dependent on Brd4, which plays a key role in cancer development . In addition to regulating transcription, Brd4 also affects many processes like DNA damage repair and checkpoint activation or telomere homoeostasis …”

PCAF, ISX, and BRD4: a maleficent alliance serving lung cancer malignancy

“…It assists in the formation of multiprotein complexes to link superenhancers and promoters [6]. p300/CBP-associated factor (PCAF) is a member of the GCN5related N-acetyltransferase family of protein acetyltransferases with HAT activity and shows ambiguous or controversial function in tumorigenesis.…”

“…Interaction of BRD4 with hyperacetylated chromatin also induces recruitment of the mediator complex via BRD4, serving as a scaffold to promote the assembly of a multi-transcription factor complex at the promoter and at superenhancers [6]. PCAF promotes acetylation (Ac) of ISX and BRD4 in the cytoplasm, which leads to the formation of a ternary complex that translocates to the nucleus.…”