GLTSCR1 Negatively Regulates BRD4-Dependent Transcription Elongation and Inhibits CRC Metastasis
GLTSCR1 Negatively Regulates BRD4-Dependent Transcription Elongation and Inhibits CRC Metastasis
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GLTSCR1 负向调节 BRD4 依赖性转录延伸并抑制 CRC 转移
DOI：
10.1002/advs.201901114
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发表时间：
2019-10-16
期刊：
影响因子：
15.1
通讯作者：
Lai, Maode
中科院分区：
文献类型：
--
作者：
Han, Fengyan;Zhang, Lei;Lai, Maode
移码突变经常发生在具有微卫星不稳定性（MSI）的结直肠癌（CRC）中，但许多MSI相关突变的性质和生物学功能尚不清楚。在这里，在胶质瘤肿瘤抑制候选区域基因1 （GLTSCR1）中发现了一个MSI移码突变，该突变产生两个c端截断蛋白。此外，GLTSCR1被证实是一种抑制结直肠癌转移的肿瘤抑制因子。GLTSCR1通过c端与溴域和溴域蛋白4的磷酸化依赖相互作用域（BRD4）结合，阻断致癌转录延伸。然而，截断的GLTSCR1易位到细胞质中并失去BRD4结合域，从而诱导RNA Pol II在Ser2位点磷酸化和Ser5位点去磷酸化，从而增加致癌转录伸长。重要的是，GLTSCR1缺陷降低了对溴结构域和额外末端结构域抑制剂的敏感性。这项研究强调了GLTSCR1-BRD4相互作用的分子机制，这是CRC的潜在治疗靶点。
Frameshift mutations frequently occur in colorectal cancer (CRC) with microsatellite instability (MSI), but the nature and biological function of many MSI-associated mutations remain elusive. Here, an MSI frameshift mutation is identified in glioma tumor suppressor candidate region gene 1 (GLTSCR1) that produces two C-terminal-truncated proteins. Additionally, GLTSCR1 is verified as a tumor suppressor that inhibits CRC metastasis. Through binding to bromodomains and the phosphorylation-dependent interaction domain of bromodomain protein 4 (BRD4) via the C-terminus, GLTSCR1 blocks oncogenic transcriptional elongation. However, truncated GLTSCR1 translocates into the cytoplasm and loses BRD4 binding domain, which induces the phosphorylation of RNA Pol II at Ser2 and dephosphorylation at Ser5, then increases oncogenic transcriptional elongation. Importantly, GLTSCR1 deficiency decreases sensitivity to bromodomain and extra terminal domain inhibitors. This study highlights the molecular mechanism of the GLTSCR1-BRD4 interaction, which is a potential therapeutic target for CRC.