TCF19/CDKN2A Regulates Glycolysis and Macrophage M2 Polarization for Osteosarcoma Progression

Osteosarcoma (OS) is the most common malignant tumor of the bone. This paper aimed to explore the mechanism of macrophage polarization and glycolysis in OS. Gene expression microarray GSE42572 for OS was downloaded from the GEO database and validated in TCGA-SARC. CDKN2A expression in OS cell lines and normal human bone osteoblasts was detected. Saos2 cells were transfected with siRNA-CDKN2A, and U2OS were transfected with pcDNA3.4-CDKN2A to knock down or upregulate CDKN2A expression to explore the role in malignant behaviors. Extracellular acidification rate, oxygen consumption rate, and glycolysis-related proteins were detected. Saos2 cells were co-incubated with THP-1 cells, and CD206 and CD86 levels were detected. The secretion of IL-10 and IL-12 by macrophages was measured. CDKN2A upstream regulatory elements were predicted by online databases, and the binding of TCF19 to the CDKN2A promoter was validated. Xenograft OS was established to verify the effect of TCF19 knockdown on OS growth in mice. CDKN2A was highly expressed in OS tissues and cell lines. CDKN2A knockdown inhibited the proliferation, migration, and invasion of Saos2 cells and promoted apoptosis and glycolysis. After CDKN2A knockdown in Saos2 cells and co-incubation with macrophages, CD206-positive cells decreased, CD86-positive cells increased, IL-10 decreased, and IL-12 increased. TCF19 was enriched on the CDKN2A promoter and promoted CDKN2A expression. Upregulation of CDKN2A by TCF19 promoted glycolysis and M2 polarization. TCF19 downregulation inhibited OS growth, metabolic reprogramming, and CDKN2A expression in OS mice. TCF19 is enriched in the CDKN2A promoter and enhances its expression, which in turn activates glycolysis and M2 polarization, ultimately promoting OS progression.