NSD2 was upregulated in osteosarcoma tissues compared with normal tissues, as well as higher in cisplatin resistant patients than in cisplatin-sensitive ones. Its knockdown enhanced apoptosis and sensitised osteosarcoma cells to cisplatin by directly decreasing H3K36me2 levels at BCL2 and SOX2 gene loci. The gene discussed is SOX2; the disease is osteosarcoma.