Abstract
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.
Highlights
Gastric cancer (GC) is an aggressive disease whose prognosis is still poor and, generally, has no specific symptoms that renders early diagnosis of this disease difficult[1]
Statistical analysis showed that bromodomain containing 4 (BRD4) expression in AGC, EGC, and PL tissues was significantly higher than that in NG tissues, whereas BRD4 expression in AGC was obviously higher than in PL, suggesting that BRD4 might play an important role in the development of GC. (Fig. 1c) In addition, Kaplan–Meier (KM) survival analysis showed that positive expression of BRD4 was significantly associated with a poor survival outcome in AGC patients (P = 0.026) (Fig. 1d)
These data indicated that BRD4 protein and mRNA levels were upregulated in human GC, and might be a potential prognostic biomarker for GC patients, providing a therapeutic rationale by targeting BRD4 in GC
Summary
Gastric cancer (GC) is an aggressive disease whose prognosis is still poor and, generally, has no specific symptoms that renders early diagnosis of this disease difficult[1]. Adding acetyl groups to lysine residues of histone proteins by histone acetyltransferases weakens polar interaction between histone proteins and DNA, relaxes chromatin structure, and drives genes more for transcription[6]. By accumulating on hyperacetylated chromatin regions as active promoters or enhancers, these proteins serve as scaffolds for recruiting TFs and multi-protein complexes that promote transcription of target genes[7], possibly changing global chromatin accessibility. Dysregulation of these BET family proteins is commonly found in a variety of diseases including cancer[6]. They are potential therapeutic targets in the development of novel anticancer drugs[8]
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