SLC9A2, suppressing by the transcription suppressor ETS1, restrains growth and invasion of osteosarcoma via inhibition of aerobic glycolysis.

Recent studies have shown that Solute Carrier Family 9 Member A2 (SLC9A2) could serve as a biomarker for cancer. However, its mechanism of action in osteosarcoma (OS) was still unclear. In this study, the data sets GSE154530 and GSE99671 were downloaded from the Gene Expression Omnibus (GEO) database, and 31 differentially expressed genes (DEGs) related to methylation were screened by bioinformatics analysis tools. Subsequently, SLC9A2 was screened as a candidate gene from DEGs, which was significantly downregulated in OS. CCK-8, transwell, western blotting and Seahorse XFe24 Cell Metabolic Analyzer assays demonstrated that overexpression of SLC9A2 could constrain OS cell proliferation, invasion, and aerobic glycolysis. Dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assays indicated ETS proto-oncogene 1 (ETS1) was a transcription suppressor of SLC9A2, and overexpression of ETS1 could promote methylation levels in specific regions of the SLC9A2 promoter. ETS1 could promote the proliferation, invasion, and aerobic glycolysis ability of OS cells, as well as tumor growth in vivo by inhibiting the expression of SLC9A2. In addition, SLC9A2, suppressing by ETS1, restrains growth and invasion of OS via inhibition of aerobic glycolysis. Thus, SLC9A2 can function as a key inhibitory factor in the aerobic glycolysis to inhibit proliferation and invasion of OS. This indicated that SLC9A2 has a potential targeted therapeutic effect on OS.

ADORA2B, transcriptionally suppressing by MYC, promotes ferroptosis of chondrocytes via inhibition of the PI3K/Akt pathway in mice with osteoarthritis.

Recent studies have shown that chondrocyte ferroptosis contributes importantly to the pathogenesis of osteoarthritis (OA). However, it is largely unknown how it is regulated. In this study, the data sets GSE167852 and GSE190184 were downloaded from the Gene Expression Omnibus (GEO) database, and 161 differentially expressed genes (DEGs) related to ferroptosis were screened by bioinformatics analysis. Subsequently, ADORA2B was screened as a candidate gene from DEGs, which was significantly upregulated in palmitic acid (PA) treated chondrocytes. CCK-8, EdU, Western blotting, and ferroptosis-related kits assays demonstrated that knockdown of ADORA2B constrained ferroptosis and promoted viability of chondrocytes. Overexpression of ADORA2B promoted ferroptosis, while the PI3K/Akt pathway inhibitor LY294002 reversed the promotion of ADORA2B on ferroptosis. Dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assays indicated MYC was a transcription suppressor of ADORA2B, and overexpression of MYC promoted the viability, and inhibited the ferroptosis of chondrocytes, while ADORA2B overexpression abated the promotion of MYC on chondrocyte viability and the inhibition on ferroptosis. In vivo experiments showed that MYC overexpression alleviated cartilage tissue damage in OA mice, which was able to reversed by ADORA2B overexpression. In summary, ADORA2B, transcriptionally suppressing by MYC, promotes ferroptosis of chondrocytes via inhibition of the PI3K/Akt pathway. Thus, ADORA2B can be used as a potential treatment target for ferroptosis-related diseases.