| NSD3, also known as WHSC1L1, is a nuclear receptor‑binding SET domain histone lysine methyltransferase of the NSD family that targets histone H3 at lysine 36 and functions as an epigenetic regulator of transcriptional programs linked to cell proliferation, survival, and lineage identity. The full‑length isoform contains two N‑terminal PWWP domains that recognize methylated histone marks and nucleic acids, multiple plant homeodomain zinc fingers that bind chromatin and regulatory proteins, and a C‑terminal catalytic SET domain flanked by pre‑SET and post‑SET regions that coordinate S‑adenosylmethionine‑dependent transfer of methyl groups to H3K36 and shape substrate specificity and product distribution across mono‑ and dimethyl states. NSD3 associates with chromatin at gene bodies and regulatory elements and catalyzes H3K36 methylation that promotes transcriptional activation by recruiting reader proteins and chromatin remodelers, counteracting repressive marks, and stabilizing an open chromatin configuration at oncogenic loci, while shorter NSD3 isoforms lacking the catalytic SET domain function as scaffolds that link bromodomain protein BRD4 and transcription factors such as MYC to chromatin‑associated complexes. Interaction with BRD4 and other transcriptional coactivators positions NSD3 within super‑enhancer and promoter hubs that coordinate high‑level expression of genes involved in cell‑cycle progression, DNA damage repair, metabolic control, and epithelial–mesenchymal transition, and NSD3‑driven H3K36 methylation modulates alternative splicing and replication‑coupled chromatin maturation in ways that influence genome stability. NSD3 expression and activity integrate upstream signaling networks, including pathways that converge on chromatin‑associated kinases and acetyltransferases, and NSD3‑dependent H3K36 methylation intersects functionally with other histone modifying enzymes, shaping combined epigenetic signatures that determine transcription factor binding and enhancer–promoter communication in both normal and transformed cells. NSD3 is recurrently amplified or overexpressed in breast, lung, head and neck, and hematologic malignancies, and NSD3‑induced H3K36 methylation activates NOTCH signaling, promotes breast cancer stemness, drives epithelial–mesenchymal transition and metastatic behavior, and contributes to resistance to targeted and cytotoxic therapies through sustained activation of oncogenic transcriptional circuits. Fusion and truncation events involving NSD3 in myeloid neoplasms produce chimeric or deregulated forms that reprogram the chromatin landscape and reinforce leukemogenic gene expression signatures, and cooperation between NSD3 and BRD4 establishes a BRD4–NSD3–MYC axis that maintains high MYC output and proliferative capacity in several tumor types. NSD3 also exerts non‑epigenetic functions by interacting with proteins such as PPP1CB to modulate STAT3 phosphorylation and glycolytic gene expression in lung adenocarcinoma. |
