Both genetic and epigenetic alterations are responsible for the stepwise initiation and progression of
cancers. Only epigenetic aberrations can be reversible, allowing the malignant cell population to revert to a more benign phenotype. The epigenetic
therapy of
cancers is emerging as an effective and valuable approach to both the
chemotherapy and the
chemoprevention of
cancer. The utilization of epigenetic targets that include
histone methyltransferase (HMTase),
Histone deacetylatase, and
DNA methyltransferase, are emerging as key therapeutic targets. The
nuclear receptor binding SET domain (NSD)
protein is a family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, and plays a critical part in
chromatin integrity as evidenced by a growing number of conditions linked to the alterations and/or amplification of NSD1, NSD2, and/or NSD3. NSD1, NSD2 and NSD3 are associated with multiple
cancers. The amplification of either NSD1 or NSD2 triggers the cellular transformation and thus is key in the early
carcinogenesis events. In most cases, reducing the levels of NSD
proteins would suppress
cancer growth. NSD1 and NSD2 were isolated as genes linked to developmental diseases, such as
Sotos syndrome and
Wolf-Hirschhorn syndrome, respectively, implying versatile aspects of the NSD
proteins. The NSD pathways, however, are not well understood. It is noteworthy that the NSD family is phylogenetically distinct compared to other known
lysine-HMTases, Here, we review the current knowledge on NSD1/NSD2/NSD3 in
tumorigenesis and prospect their special value for developing novel anticancer drugs.