Zhou Siqi, Zhang Shu, Wang Lei, Huang Shuling, Yuan Yue, Yang Jie, Wang Hui, Li Xihan, Wang Pin, Zhou Lin, Yang Jun, Xu Yuemei, Gao Huan, Zhang Yixuan, Lv Ying, Zou Xiaoping
Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing, 210008, China.
Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.
Oncogenesis. 2020 Mar 10;9(3):33. doi: 10.1038/s41389-020-0218-z.
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.
染色质可及性对肿瘤发展至关重要，但其机制仍不清楚。作为染色质重塑的关键调节因子，BRD4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）中的全局转录在很大程度上仍不清楚。在本研究中，我们发现BRD4在GC组织中高表达，且与预后不良显著相关。JQ1在体外抑制GC细胞的增殖并诱导其凋亡。此外，JQ1通过诱导上皮-间质转化（MET）抑制癌细胞的迁移和侵袭。值得注意的是，一种使用测序技术检测转座酶可及染色质的方法（ATAC-seq）数据显示，JQ1明显下调了GC细胞的染色质可及性，且差异可及区域高度富集RUNX2结合基序。对ATAC-seq和RNA-seq数据的联合分析发现NID1是JQ1的下游靶点，且JQ1降低了GC细胞中NID1的表达。染色质免疫沉淀、荧光素酶报告基因检测和拯救实验均证实RUNX2/NID1轴是JQ1抑制GC细胞转移的原因。此外，GC组织中NID1的高表达也预示着癌症患者的生存预后不良，且NID1基因敲低通过部分诱导MET抑制癌细胞的迁移和侵袭。最后，体内模型表明JQ1可抑制GC生长并抑制癌症转移。总之，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也是进展期GC患者的一个新的治疗靶点。
