Chromatin Looping Shapes KLF5-Dependent Transcriptional Programs in Human Epithelial Cancers.
Chromatin Looping Shapes KLF5-Dependent Transcriptional Programs in Human Epithelial Cancers.
复制标题
DOI：
10.1158/0008-5472.can-20-1287
复制
发表时间：
2020-12-15
期刊：
影响因子：
11.2
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Liu Y;Guo B;Aguilera-Jimenez E;Chu VS;Zhou J;Wu Z;Francis JM;Yang X;Choi PS;Bailey SD;Zhang X
转录因子的激活是癌症中的关键驱动事件。我们和其他人最近报道了Krüppel样转录因子KLF 5在多种上皮癌类型中被激活，包括鳞状细胞癌和胃肠道腺癌，但这种激活的功能后果和潜在机制在很大程度上仍然未知。在这里，我们证明了KLF 5的激活导致这些癌症类型的强烈选择性KLF 5依赖性。KLF 5结合谱系特异性调控元件并激活癌细胞必需的基因表达程序。HiChIP分析显示，多个远端KLF 5结合事件聚集并协同激活单个靶基因。免疫沉淀-质谱分析表明，KLF 5与其他转录因子如TP 63和YAP 1以及CBP/EP 300乙酰转移酶复合物相互作用。此外，KLF 5引导CBP/EP 300复合物增加H3 K27的乙酰化，这反过来增强了溴结构域蛋白BRD 4向染色质的募集。3D染色质结构聚集KLF 5依赖性BRD 4结合以激活KLF 5靶基因处的聚合酶II（POL 2）延伸，这赋予了对蛋白水解靶向嵌合体（PROTAC）诱导的BRD 4降解的转录脆弱性。我们的研究表明，KLF 5通过3D染色质环激活癌症相关基因，在多种上皮癌中发挥重要作用，为靶向KLF 5通路提供了基于证据的理论基础。
Activation of transcription factors is a key driver event in cancer. We and others have recently reported that the Krüppel-like transcription factor KLF5 is activated in multiple epithelial cancer types including squamous cancer and gastrointestinal adenocarcinoma, yet the functional consequences and the underlying mechanisms of this activation remain largely unknown. Here we demonstrate that activation of KLF5 results in strongly selective KLF5 dependency for these cancer types. KLF5 bound lineage-specific regulatory elements and activated gene expression programs essential to cancer cells. HiChIP analysis revealed that multiple distal KLF5 binding events cluster and synergize to activate individual target genes. Immunoprecipitation-mass spectrometry assays showed that KLF5 interacts with other transcription factors such as TP63 and YAP1, as well as the CBP/EP300 acetyltransferase complex. Furthermore, KLF5 guided the CBP/EP300 complex to increase acetylation of H3K27, which in turn enhanced recruitment of the bromodomain protein BRD4 to chromatin. The 3D chromatin architecture aggregated KLF5-dependent BRD4 binding to activate Polymerase II (POL2) elongation at KLF5-target genes, which conferred a transcriptional vulnerability to proteolysis-targeting chimera (PROTAC)-induced degradation of BRD4. Our study demonstrates that KLF5 plays an essential role in multiple epithelial cancers by activating cancer-related genes through 3D chromatin loops, providing an evidence-based rationale for targeting the KLF5 pathway.