BRD4
小结
BRD4是致癌基因，编码蛋白为bromodomain and extraterminal (BET)蛋白家族成员，在特定基因增强子元件的转录激活和延伸中具有重要作用。BRD4结合乙酰化组蛋白赖氨酸基序，并协助招募转录调节复合物的成员，包括P-TEFb和Mediator，这对于PoIII依赖性转录延伸是必需的。BRD4已被证明在炎症、病毒基因表达和心力衰竭中发挥作用。被称为“超级增强子”的调控元件的一个子集与高水平的BRD4结合，并且特别容易通过小分子形成对BRD4抑制（BETi）的转录扰动。例如，BETi通过其超级增强子显著降低MYC下游活性。因此，实验数据表明，MYC驱动的癌症对BETi特别敏感，包括多发性骨髓瘤和髓母细胞瘤。染色体BRD4-NUT融合产物在大多数NUT中线癌中是驱动因素，且对BETi敏感。在乳腺癌中BRD4的过度磷酸化可导致对BETi的抗性，SPOP突变可导致前列腺癌中的BRD4稳定。
BRD4 is a member of the bromodomain and extraterminal (BET) family of proteins, and is important in transcriptional activation and elongation at specific gene enhancer elements. BRD4 binds to acetylated histone lysine motifs and helps recruit members of the transcriptional regulator complex, including P-TEFb and Mediator, which are necessary for PolII-dependent transcriptional elongation. BRD4 has been shown to have a role in inflammation, viral gene expression and heart failure. A subset of regulatory elements termed 'super-enhancers' are bound by high levels of BRD4 and are particularly prone to transcriptional perturbations of BRD4 inhibition (BETi) via small molecules. For example, BETi results in significant reduction of MYC downstream activity via its super-enhancer. As such, experimental data has shown that MYC-driven cancers are particularly sensitive to BETi, including multiple myeloma and medulloblastoma. A chromosomal BRD4-NUT fusion product is a driver of disease in most cases of NUT midline carcinoma and is sensitive to BETi. Resistance to BETi can arise due to BRD4 hyperphosphorylation in breast cancer, and SPOP mutations, which can lead to BRD4 stabilization in prostate cancer.