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Opposing Functions of BRD4 Isoforms in Breast Cancer.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-05-23 , DOI: 10.1016/j.molcel.2020.04.034
Shwu-Yuan Wu 1 , Chien-Fei Lee 2 , Hsien-Tsung Lai 2 , Cheng-Tai Yu 3 , Ji-Eun Lee 4 , Hao Zuo 5 , Sophia Y Tsai 3 , Ming-Jer Tsai 3 , Kai Ge 4 , Yihong Wan 6 , Cheng-Ming Chiang 7
Affiliation  

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.



中文翻译:

BRD4亚型在乳腺癌中的相反功能。

在正在进行的主要破坏BRD4调节的转录程序的临床试验中,含溴结构域的蛋白4(BRD4)是癌症的治疗靶标。BRD4在癌症中的作用主要归因于丰富的长同工型(BRD4-L)。在这里,我们通过同工型特异性敲除和内源蛋白检测以及转基因表达显示出,较不丰富的BRD4短同工型(BRD4-S)具有致癌性,而BRD4-L在乳腺癌细胞的增殖和迁移中也具​​有肿瘤抑制作用。由于乳腺肿瘤的形成和转移。通过整合的RNA序列,全基因组ChIP序列以及CUT&RUN关联分析,我们确定Engrailed-1(EN1)同源框转录因子是关键的BRD4-S调控因子,尤其是在三阴性乳腺癌中。BRD4-S和EN1通过增强与癌症相关的基因和途径的调控,共同调节细胞外基质(ECM)相关的基质网络,包括II型胱抑素基因簇,粘蛋白5和组织蛋白酶基因座。我们的工作凸显了靶向疗法对于BRD4的致癌性(而不是肿瘤抑制性)活性的重要性。

更新日期:2020-06-18
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