Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cell. 2020 Jun 18;78(6):1114-1132.e10. doi: 10.1016/j.molcel.2020.04.034. Epub 2020 May 23.
Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4.
溴结构域蛋白 4（BRD4）是正在进行的临床试验中的癌症治疗靶点，主要通过破坏 BRD4 调节的转录程序来发挥作用。BRD4 在癌症中的作用主要归因于丰富的长亚型（BRD4-L）。在这里，我们通过特异性敲低和内源性蛋白质检测，以及转基因表达，证明较少的 BRD4 短亚型（BRD4-S）在乳腺癌细胞增殖和迁移以及乳腺肿瘤形成和转移中具有致癌作用，而 BRD4-L 则具有肿瘤抑制作用。通过整合 RNA-seq、全基因组 ChIP-seq 和 CUT&RUN 关联分析，我们确定了 Engrailed-1（EN1）同源盒转录因子是 BRD4-S 的关键共调节因子，特别是在三阴性乳腺癌中。BRD4-S 和 EN1 通过增强子调节与癌症相关的基因和通路，共同调节细胞外基质（ECM）相关的基质组网络，包括 II 型半胱氨酸蛋白酶基因簇、粘蛋白 5 和组织蛋白酶基因座。我们的工作强调了针对 BRD4 的致癌而非肿瘤抑制活性的靶向治疗的重要性。
