BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling
BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling
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BET 蛋白抑制剂 JQ1 通过失活 RUNX2/NID1 信号下调染色质可及性并抑制胃癌转移
DOI：
10.1038/s41389-020-0218-z
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发表时间：
2020-03-10
期刊：
影响因子：
6.2
通讯作者：
Zou, Xiaoping
中科院分区：
文献类型：
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作者：
Zhou, Siqi;Zhang, Shu;Zou, Xiaoping
染色质可及性对肿瘤的发展至关重要，其机制尚不清楚。BRD4作为染色质重塑的重要调控因子，通过调控多个基因促进肿瘤进展。作为BRD4的小分子抑制剂，JQ1对多种人类癌症具有强大的化疗活性。然而，JQ1是否具有潜在的抗肿瘤作用，以及JQ1如何调节胃癌（GC）的全局转录，在很大程度上仍然未知。在本研究中，我们发现BRD4在GC组织中高表达，并与不良预后显著相关。JQ1在体外抑制胃癌细胞增殖并诱导凋亡。JQ1通过诱导MET抑制癌细胞的迁移和侵袭。值得注意的是，利用测序（ATAC-seq）数据对转座酶可及染色质进行的分析显示，JQ1明显下调了GC细胞的染色质可及性，runx2结合基序的差异可及区域高度富集。结合ATAC-seq和RNA-seq数据分析发现NID1是JQ1的下游靶点，JQ1降低了NID1在GC细胞中的表达。染色质免疫沉淀、荧光素酶报告基因测定和抢救实验均证实RUNX2/NID1轴与jq1抑制GC细胞转移有关。此外，GC组织中NID1的高表达也预示着癌症患者的生存预后较差，NID1敲低通过部分诱导MET阻止癌细胞的迁移和侵袭。最后，体内模型显示JQ1能抑制胃癌生长并抑制肿瘤转移。综上所述，JQ1通过下调染色质可及性和使RUNX2/NID1信号失活来抑制GC的恶性进展。此外，NID1也是进行性胃癌患者新的治疗靶点。
Chromatin accessibility is critical for tumor development, whose mechanisms remain unclear. As a crucial regulator for chromatin remodeling, BRD4 promotes tumor progression by regulating multiple genes. As a small-molecule inhibitor of BRD4, JQ1 has potent chemotherapeutic activity against various human cancers. However, whether JQ1 has potential anti-tumor effects and how JQ1 regulates global transcription in gastric cancer (GC) remain largely unknown. In this research, we found BRD4 was highly expressed in GC tissues and was significantly associated with poor prognosis. JQ1 inhibited the proliferation and induced apoptosis of GC cells in vitro. Besides, JQ1 suppressed the migration and invasion of cancer cells by inducing MET. Notably, an assay for transposase-accessible chromatin using sequencing (ATAC-seq) data showed that JQ1 obviously downregulated the chromatin accessibility of GC cells and differentially accessible regions were highly enriched for RUNX2-binding motifs. Combinational analysis of ATAC-seq and RNA-seq data discovered NID1 as the downstream target of JQ1 and JQ1 reduced NID1 expression in GC cells. Chromatin immunoprecipitation, luciferase reporter gene assay, and rescue experiments all confirmed that RUNX2/NID1 axis was responsible for JQ1-inhibiting metastasis of GC cells. What’s more, high expression of NID1 in GC tissues also predicted poor survival outcome of cancer patients and NID1 knockdown prohibited migration and invasion of cancer cells via partially inducing MET. Finally, in vivo models showed that JQ1 prevented GC growth and suppressed cancer metastasis. In conclusion, JQ1 inhibits the malignant progression of GC by downregulating chromatin accessibility and inactivating RUNX2/NID1 signaling. In addition, NID1 is also a novel therapeutic target for progressive GC patients.