NSD2, a member of the Nuclear SET Domain (NSD) family, is a histone methyltransferase responsible for dimethylating histone 3 at lysine 36 (H3K36me2). This epigenetic mark is involved in maintaining chromatin integrity and regulating genes related to cell division, apoptosis, DNA repair, and epithelial-mesenchymal transition (EMT) [3,4].

In lung adenocarcinoma (LUAD), the in vivo expression of a hyperactive NSD2 variant (NSD2E1099K) accelerates tumor progression, while NSD2 loss via a CRISPRi-based system strongly attenuates tumor growth. Also, NSD2 knockdown blocks the neoplastic growth of patient-derived xenografts (PDXs) from primary LUAD. Combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors, identifying NSD2 as a therapeutic target [1]. In colon cancer, NSD2 overexpression enhances tumor metastasis by activating Rac1 signaling through methylating Tiam1 at K724 [2]. In neuroendocrine prostate cancer (CRPC-NE), NSD2 maintains lineage plasticity and castration-resistance. CRISPR/Cas9 targeting of NSD2 or expression of a dominant-negative oncohistone H3.3K36M mutant can reverse these phenotypes and restore responsiveness to the AR inhibitor enzalutamide [5].

In summary, NSD2 is crucial in the pathogenesis and progression of multiple cancers, including LUAD, colon cancer, and CRPC-NE. The use of gene knockout or knockdown models in these studies has revealed its key role in promoting tumorigenesis and metastasis, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Sengupta, Deepanwita, Zeng, Liyong, Li, Yumei, Mazur, Pawel K, Gozani, Or. 2021. NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis. In Molecular cell, 81, 4481-4492.e9. doi:10.1016/j.molcel.2021.08.034. https://pubmed.ncbi.nlm.nih.gov/34555356/

2. Song, Da, Hu, Fuqing, Huang, Changsheng, Hu, Junbo, Wang, Guihua. 2023. Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2305684120. doi:10.1073/pnas.2305684120. https://pubmed.ncbi.nlm.nih.gov/38113258/

3. Azagra, Alba, Cobaleda, César. 2022. NSD2 as a Promising Target in Hematological Disorders. In International journal of molecular sciences, 23, . doi:10.3390/ijms231911075. https://pubmed.ncbi.nlm.nih.gov/36232375/

4. Topchu, Iuliia, Pangeni, Rajendra P, Bychkov, Igor, Karanicolas, John, Boumber, Yanis. 2022. The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors. In Cellular and molecular life sciences : CMLS, 79, 285. doi:10.1007/s00018-022-04321-2. https://pubmed.ncbi.nlm.nih.gov/35532818/

5. Li, Jia J, Vasciaveo, Alessandro, Karagiannis, Dimitrios, Lu, Chao, Shen, Michael M. 2023. NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.07.18.549585. https://pubmed.ncbi.nlm.nih.gov/37502956/