7wwz | pdb_00007wwz
BRD4-BD1 complexed with NEO2734
Structural highlights
Disease[BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2] Function[BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedCUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC. Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer.,Ji D, Shang G, Wei E, Jia Y, Wang C, Zhang Q, Zeng L Oncogene. 2022 Jun;41(23):3251-3262. doi: 10.1038/s41388-022-02327-5. Epub 2022, May 5. PMID:35513563[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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