SIGNIFICANCE: These findings reveal a novel posttranscriptional regulatory function of the epigenetic reader BRD4 in cancer metastasis via stabilizing Snail, with immediate translational implication for treating metastatic malignancies with clinically available bromodomain inhibitors.
Our discovery of a protein (S-CAP) in Myriapods and Chelicerates that contains a motif similar to the Su(H)-binding domain in Hairless has revealed a likely evolutionary connection between Hairless and Metastasis-associated (MTA) protein, a component of the NuRD complex.
BRD4, a coregulator of gene transcription, controls migration and invasion through transcription of AHNAK, a large scaffolding protein linked to promotion of metastasis in a diverse set of cancers.
BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis <i>in vivo</i>.
Our findings highlight the importance of acetylation signaling in the SPZ1-TWIST1-BRD4 axis in the mediation of EMT and its regulation during tumor initiation and metastasis.
Pharmacologic inhibition of BRD4 using JQ1 and/or PI3K using dual PI3K/BRD4 inhibitor SF2523 (previously reported by our group as a potent inhibitor to block tumor growth and metastasis in various cancer models) suppresses tumor growth in syngeneic and spontaneous murine cancer models; reduces infiltration of myeloid-derived suppressor cells; blocks polarization of immunosuppressive MΘs; restores CD8<sup>+</sup> T-cell activity; and stimulates antitumor immune responses.
In the present study, it was demonstrated that BRD4 expression levels were significantly increased in cancerous prostate tissue specimens and cells, which were associated with clinical stage and metastasis.
Here, we found that BRD4 expression was significantly upregulated in NSCLC tissues and NSCLC cell lines with higher invasion and metastasis potentials.
Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.
Because abnormal stem cell self-renewal is frequently observed during tumor formation and metastasis, the aberrant stem cell-like proliferation associated with BRD4 dysregulation observed in NMC carcinoma may have implications for studying the oncogenic mechanism of other BRD4-associated tumors.
To gain insights into why BET inhibition was ineffective against metastases the pro-metastatic short isoform of BRD4 was characterized using mass spectrometry and cellular fractionation.
Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion.
Further in vitro analysis shows that Brd4 modulates extracellular matrix gene expression, a class of genes frequently present in metastasis-predictive gene signatures.
Brd4 and Rrp1b appear to form a central node within this network, which likely is a consequence of their physical interaction with the metastasis efficiency modifier Sipa1.