NSD Histone Methyltransferases in Solid Tumors: Biological Functions, Oncogenic Mechanisms and Therapeutic Targeting

Abstract

Epigenetic dysregulation is a defining feature of solid tumors. Among epigenetic regulators, the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases, comprising NSD1, NSD2, and NSD3, have emerged as critical mediators of oncogenic chromatin remodeling and transcriptional regulation. These enzymes primarily catalyze histone H3 lysine 36 (H3K36) methylation, thereby regulating chromatin accessibility, transcriptional programs, DNA damage repair, and genome stability. Aberrant expression, mutation, amplification, and chromosomal rearrangement of NSD family members have been identified across tumors, establishing them as key epigenetic drivers of malignancy. Accumulating evidence demonstrates that NSD proteins promote multiple hallmarks of cancer, including sustained proliferative signaling, invasion and metastasis, immune evasion, metabolic reprogramming, genome instability, and therapeutic resistance. Although NSD proteins share overlapping catalytic functions, each exhibit distinct biological roles and mechanisms of dysregulation in solid tumors. Advances in structural biology, medicinal chemistry, and targeted protein degradation have accelerated the development of selective NSD inhibitors, chromatin-reader antagonists, and proteolysis-targeting chimeras (PROTACs), establishing the feasibility of pharmacologically targeting NSD-dependent epigenetic pathways. In this review, we summarize the biological functions of the NSD family, discuss their oncogenic mechanisms in solid tumors, and highlight recent progress in therapeutic targeting.