Gastric cancer prognoses are persistently poor due to cancer's penchant to metastasize. As a crucial regulator of signal transducer and activator of transcription (STAT3) signaling, sirtuin 1's (SIRT1) function in gastric cancer has not been well understood. Here, we report upregulated expression of SIRT1 in tissues isolated from gastric cancer patients. However, we show that the depletion of SIRT1‐mediated enhanced cancer cell proliferation and metastasis, and resulted in the enrichment of phosphorylated STAT3, acetylated STAT3, and matrix metalloproteinase 13 (MMP‐13) in both in vivo and in vitro experiments. Additionally, we demonstrate that small interfering RNAs targeting the production of STAT3, AG490, and CL‐821983 in cancer cells depleted of SIRT1 reduce metastasis. Our findings indicate that MMP‐13 expression is associated with lymph node metastasis and poor survival outcomes in gastric cancer patients. In vivo models also showed that depleted SIRT1 promoted gastric cancer growth via the STAT3/MMP‐13 axis. In conclusion, SIRT1 depletion encourages gastric cancer progression through the activation of STAT3/MMP‐13 signaling, suggesting that SIRT1 may function as a tumor suppressor. We postulate that the upregulation of SIRT1 in gastric cancer patients may be the result of a feedback mechanism that aims to oppose the damaging effects of STAT3 signaling. As such, SIRT1 activators could potentially serve as preventive and therapeutic treatments for metastatic gastric cancer.

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. Oncogenesis 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,;

Panax notoginseng saponins (PNS) are active extracts obtained from the P. notoginseng plant. PNS exhibit various anti-inflammatory, anti-oxidant and anti-aging pharmacological properties in some cells. However, the effects of PNS on senescence and apoptosis in chondrocytes have not been studied to date. In the present study, whether PNS could limit tumor necrosis factor (TNF)-α-induced senescence and apoptosis in chondrocytes and whether they could slow down cartilage degeneration in a surgery-induced rat osteoarthritis (OA) model by regulating the phosphatidyl inositol 3 kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling pathway was examined. A potential mechanism underlying these effects was further elucidated. The present in vitro experiments showed that PNS significantly inhibited senescence and apoptosis in OA chondrocytes and prevented a decrease in the mitochondrial membrane potential and excessive mitochondrial permeability. In addition, the expression levels of autophagy-related proteins and the anti-apoptotic protein Bcl-2 were significantly increased in PNS-treated OA chondrocytes, but the expression levels of Bax and caspase-3 were decreased; these effects were concentration-dependent. TNF-α significantly increased the expression of p-PI3K/p-AKT/p-mTOR in OA chondrocytes, whereas PNS reduced PI3K, AKT and mTOR phosphorylation. The results of the in vivo experiments demonstrated that PNS significantly inhibited the PI3K-AKT-mTOR signaling pathway and collagen II degradation, as well as reduced matrix metalloproteinase (MMP)-3 and MMP-13 expression in chondrocytes in a rat OA model, thus attenuating cartilage destruction in OA. The results obtained in the rat model were consistent with the in vitro experimental results. Furthermore, histological analyses and ultrastructural observations confirmed these results. Taken together, the results of the present study demonstrated that PNS may protect osteoarthritic chondrocytes from senescence and apoptosis by inhibiting the PI3K-AKT pathway, thus delaying the degradation of articular cartilage.