Epigenome dysregulation resulting from NSD1 mutation in head and neck squamous cell carcinoma

Abstract

Epigenetic dysregulation has emerged as an important mechanism of oncogenesis. To develop targeted treatments, it is important to understand the epigenetic and transcriptomic consequences of mutations in epigenetic modifier genes. Recently, mutations in the histone methyltransferase gene NSD1 have been identified in a subset of head and neck squamous cell carcinomas (HNSCCs)one of the most common and deadly cancers. Here, we use whole (epi)genome approaches and genome editing to dissect the downstream effects of loss of NSD1 in HNSCC. We demonstrate that NSD1 mutations are directly responsible for the loss of intergenic H3K36me2 domains, followed by loss of DNA methylation, and gain of H3K27me3 in the affected genomic regions. We further show that those regions are enriched in cisregulatory elements and that subsequent loss of H3K27ac correlates with reduced expression of their target genes. Our analysis identifies genes and pathways affected by the loss of NSD1 and paves the way to further understanding the interplay among chromatin modifications in cancer.regions defined in Fig. 3a as "cluster B"); median values are shown at the top. e Spearman correlation of differential enrichment between NSD1-WT vs KO and WT vs MT.

The interplay between DNA and histone methylation: molecular mechanisms and disease implications

“…Second, although somatic mutations affecting DNMTs and TETs are rare in solid tumors, mutations in histone-modifying enzymes and histones themselves can have a direct effect on reprogramming DNA methylome. As described above, NSD1 mutations and deletions in squamous cell carcinomas result in global DNA hypomethylation as a consequence of defective DNMT3A recruitment by H3K36me2 (Lee & Wiemels, 2016;Brennan et al, 2017;Papillon-Cavanagh et al, 2017;Bui et al, 2018;Weinberg et al, 2019;Farhangdoost et al, 2021). Histone H3 lysine 36 to methionine (H3K36M) mutations deplete H3K36 methylation by inhibiting the catalytic activities of H3K36 methyltransferases, and H3K36M mutations are mutually exclusive with NSD1 loss-of-function mutations in head and neck squamous cell carcinomas (Lu et al, 2016;Papillon-Cavanagh et al, 2017).…”

Lysine Methyltransferase NSD1 and Cancers: Any Role in Melanoma?

“…In HPV-negative HNSCC, NSD1 in vitro suppression led to the reduction of intergenic H3K36me2 domains followed by DNA hypomethylation, gain in H3K27me3 and, loss of the active mark H3K27ac, thereby affecting transcriptional activity. The aforementioned epigenome reprogramming led to the downregulation of putative genes associated with tumor immunity, signaling and plasticity [56,57].…”