SATB2, a DNA-binding protein, specifically targets nuclear matrix attachment regions, playing roles in transcriptional regulation and chromatin remodeling, particularly in craniofacial, neural, and osteoblast differentiation. SATB2 protein is highly expressed in brain, digestive tract, bone marrow, and immune system, but not in other tissues. In cancers, SATB2 is highly expressed in colorectal cancer, but weakly or not expressed in gastric adenocarcinoma, lung adenocarcinoma, and ovarian cancer. For tumors of unknown origin, SATB2 positivity indicates a lower gastrointestinal tract source. Recent studies show SATB2 is a marker of osteoblast differentiation, useful for osteosarcoma diagnosis.