NSD1: A Lysine Methyltransferase between Developmental Disorders and Cancer

Abstract

Recurrent epigenomic alterations associated with multiple human pathologies have increased the interest in the nuclear receptor binding SET domain protein 1 (NSD1) lysine methyltransferase. Here, we review the current knowledge about the biochemistry, cellular function and role of NSD1 in human diseases. Several studies have shown that NSD1 controls gene expression by methylation of lysine 36 of histone 3 (H3K36me1/2) in a complex crosstalk with de novo DNA methylation. Inactivation in flies and mice revealed that NSD1 is essential for normal development and that it regulates multiple cell type-specific functions by interfering with transcriptional master regulators. In humans, putative loss of function NSD1 mutations characterize developmental syndromes, such as SOTOS, as well as cancer from different organs. In pediatric hematological malignancies, a recurrent chromosomal translocation forms a NUP98-NSD1 fusion with SET-dependent leukemogenic activity, which seems targetable by small molecule inhibitors. To treat or prevent diseases driven by aberrant NSD1 activity, future research will need to pinpoint the mechanistic correlation between the NSD1 gene dosage and/or mutational status with development, homeostasis, and malignant transformation.

Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer

“…NSD1 (histone H3 lysine 36 methyltransferase) is involved in chromatin organization and is considered an epigenetic regulator [40]. Somatic loss-of-function NSD1 mutations are among the most prevalent lesions in human head and neck and lung squamous cell carcinomas, neuroblastomas and glioblastomas, and NSD1 gene silencing has been detected in clear cell renal cell carcinoma and urogenital cancers (reviewed by Tauchmann and Schwaller [40]). Little is known regarding the role of NSD1 in colorectal cancer; however, publicly available data indicate that NSD1 somatic alterations occur in 4% of colon cancers (source: cBioPortal; accessed Jan. 2022).…”

Nuclear Location Bias of HCAR1 Drives Cancer Malignancy through Numerous Routes

“…While these chromatin remodelers are significantly miss-regulated in many cancers (Lu and Roberts, 2013),(Prendergast et al ., 2020),(Li et al ., 2021), N-HCAR1 activated by higher concentration of lactate seen in tumor (Warburg effect) could alter their activity (in favor of cancer promotion). Interestingly, inactive N-HCAR1 also interacted with NSD1, a histone methyltransferase known to bind to different nuclear receptors (including estrogen, thyroid, retinoic acid, and retinoid receptors) (Tauchmann and Schwaller, 2021); since NSD1 is frequently mis-regulated in cancers (Tauchmann and Schwaller, 2021) it is tempting to speculate that metabolic rewiring could cause epigenomic alterations in favor of cancer malignancy. Concordantly, our genome-wide association study shows how N-HCAR1 could directly promote expression of genes involved in migration potentially through these epigenetic modulations.…”

The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation

“…The nuclear receptor binding SET domain protein 2 (NSD2) (also known as MMSET, and WHSC1) (Lam et al, 2022) and its human paralogs NSD1 (also known as KMT3B) (Tauchmann and Schwaller, 2021) and NSD3 (WHSC1L1) (Rathert, 2021), are Su(var)3–9, Enhancer-of-zeste, Trithorax (SET) domain containing PKMTs (Lam et al, 2022; Rayasam et al, 2003). All NSD enzymes share a similar domain organization.…”