BRD4 Short Isoform Interacts with RRP1B, SIPA1 and Components of the LINC Complex at the Inner Face of the Nuclear Membrane

Recent studies suggest that BET inhibitors are effective anti-cancer therapeutics. Here we show that BET inhibitors are effective against murine primary mammary tumors, but not pulmonary metastases. BRD4, a target of BET inhibitors, encodes two isoforms with opposite effects on tumor progression. 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. Our data show that the pro-metastatic short isoform interacts with the LINC complex and the metastasis-associated proteins RRP1B and SIPA1 at the inner face of the nuclear membrane. Furthermore, histone binding arrays revealed that the short isoform has a broader acetylated histone binding pattern relative to the long isoform. These differential biochemical and nuclear localization properties revealed in our study provide novel insights into the opposing roles of BRD4 isoforms in metastatic breast cancer progression.已有研究表明，BET抑制剂（BET inhibitors）是有效的抗癌治疗药物。本研究显示，BET抑制剂对小鼠原发性乳腺肿瘤具有疗效，但对肺转移瘤无效。BRD4作为BET抑制剂的靶点，其编码的两种亚型对肿瘤进展具有截然相反的调控作用。为探究BET抑制剂对转移瘤无效的原因，本研究通过质谱分析与细胞分级分离技术，对BRD4的促转移短亚型进行了表征。研究数据显示，该促转移短亚型在核膜内侧与LINC复合物以及转移相关蛋白RRP1B和SIPA1发生相互作用。此外，组蛋白结合阵列分析结果表明，相较于长亚型，短亚型的乙酰化组蛋白结合谱更为广泛。本研究揭示的这些差异化生化特性与核定位特征，为理解BRD4亚型在转移性乳腺癌进展中的对立作用提供了全新视角。