Abstract 3650: A noncanonical histone target of NSD2 may contribute to oncogenesis

Abstract

Abstract The NSD family of protein lysine methyltransferases (PKMTs), containing members NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, cause epigenetic aberrations when dysregulated in cancer and are thus attractive therapeutic targets. These enzymes share a canonical activity catalyzing the dimethylation of histone 3 lysine 36 (H3K36me2), a mark associated with gene activation. In cancer, these enzymes are often overexpressed, amplified, or mutated, resulting in increased global H3K36me2 and transcriptional activation. In addition to transcriptional regulation, NSD2 has also been reported to be involved in pathways such as DNA replication and repair, which cannot be readily rationalized via its H3K36 methylation activity. This suggests that NSD2 has unidentified substrates that carry out its additional biological function(s), nonredundant with NSD1/3. Furthermore, NSD2 has a recurring glutamate to lysine mutation in the catalytic SET domain at 1099 (E1099K), which results in gain-of-function activity on H3K36. Our preliminary data has shown that NSD2 has noncanonical histone targets that are augmented by NSD2 E1099K to drive oncogenesis. We are using cell based approaches to dissect its downstream biology to reveal NSD2's oncogenic potential. Citation Format: Nicole Weiss, Minkui Luo. A noncanonical histone target of NSD2 may contribute to oncogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3650.