Histone-lysine N-methyltransferase, H3 lysine-36 specific (NSD1) (NSD1)

NSD1 (Nuclear receptor-binding SET domain-containing protein 1) is a histone methyltransferase that primarily catalyzes the mono- and di-methylation of lysine 36 on histone H3 (H3K36me1/2) (UniProt Q96L73; NIH PMC7463119). This epigenetic modification is crucial for transcriptional regulation, chromatin organization, and the recruitment of DNA methyltransferases like DNMT3A to intergenic regions (NIH PMC8395156; ResearchGate 360198444). NSD1 plays a vital role in normal human development, and its haploinsufficiency is the primary cause of Sotos syndrome, a condition characterized by overgrowth and intellectual disability (MedlinePlus Genetics; NIH PMC8395156). In oncology, NSD1 is frequently involved in chromosomal translocations, most notably the NUP98-NSD1 fusion found in aggressive pediatric acute myeloid leukemia (AML), where it drives the expression of oncogenic genes like HOXA9 (NIH PMC7463119; MedlinePlus Genetics). Conversely, loss-of-function mutations in NSD1 are common in head and neck squamous cell carcinomas (HNSCC), leading to altered DNA methylation patterns and transcriptional deregulation (NIH PMC8395156; NIH PMC8141357). Therapeutic strategies targeting NSD1 focus on small-molecule inhibitors of its catalytic SET domain, such as the lead compound BT5, to disrupt oncogenic gene expression in fusion-positive leukemias (NIH PMC7463119).

Other names

Nuclear receptor-binding SET domain-containing protein 1KMT3BARA267H3-K36-HMTaseAndrogen receptor coactivator 267 kDa proteinLysine N-methyltransferase 3B

Irreversible inhibition of the catalytic SET domain to prevent the mono- and di-methylation of histone H3 lysine 36 (H3K36), thereby downregulating oncogenic target genes such as HOXA9 and MEIS1.