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摘要: NSD3是具有致癌作用的组蛋白赖氨酸甲基转移酶（HKMTases）NSD（核受体结合SET结构域蛋白）家族的一员。近期许多研究表明NSD3在乳腺癌、急性髓性白血病、坚果中线癌、肺癌等多种恶性肿瘤中有促进肿瘤发生的作用，可与NUP98、NUT融合或与BRD4、CHD8、MYC等相互作用，形成致癌复合物；也可以通过调控H3K36me2水平或EGFR（K721）甲基化，加速细胞周期进程，促进肿瘤发生。NSD3不仅参与肿瘤的发生，还与肿瘤的不良预后及侵袭能力有关。本文对NSD3最新的研究进展进行归纳总结，探讨NSD3在肿瘤发生中的作用及潜在的应用前景。
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关键词:
- NSD3 /
- 组蛋白赖氨酸甲基转移酶 /
- 肿瘤
Abstract: NSD3 is a member of the nuclear receptor-binding SET domain (NSD) family of histone lysine methyltransferases (HKMTases), which play important roles in tumorigenesis. Many recent studies have shown that NSD3 can promote the occurrence of various malignant tumors such as breast cancer, acute myeloid leukemia, NUT midline cancer, and lung cancer. It can fuse with NUP98 and NUT, or interact with BRD4, CHD8, and MYC to form carcinogenic complexes. It can also accelerate cell cycle progression and promote tumorigenesis by regulating the levels of H3K36me2 or EGFR (K721) methylation. NSD3 is not only involved in the occurrence of tumors but also related to the poor prognosis and enhanced invasive ability of tumors. In this paper, the current progress of research regarding NSD3 is summarized and the role of NSD3 in tumorigenesis and its potential application prospects are explored.-
Key words:
- NSD3 /
- histone lysine methyltransferase /
- neoplasm
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图 1 组蛋白赖氨酸甲基转移酶NSD3结构图
PWWP：脯氨酸-色氨酸-色氨酸-脯氨酸结构域；PHD：锌指结构域；SET：前SET结构域、核心SET结构域、后置SET结构域；PHD5-C5HCH：第5个锌指结构域和富含半胱氨酸-组氨酸结构
表 1 与组蛋白甲基转移酶NSD3相关的肿瘤
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[1] Han X, Piao L, Zhuang Q, et al. The role of histone lysine methyltransferase NSD3 in cancer[J]. Onco Targets Ther, 2018, 1(1):3847-3852. http://europepmc.org/articles/PMC6038882/ [2] Angrand PO, Apiou F, Stewart AF, et al. NSD3, a new SET domaincontaining gene, maps to 8p12 and is amplified in human breast cancer cell lines[J]. Genomics, 2001, 74(1):79-88. doi: 10.1006/geno.2001.6524 [3] Dillon SC, Zhang X, Trievel RC, et al. The SET-domain protein superfamily:protein lysine methyltransferases[J]. Genome Biol, 2005, 6(8):227. doi: 10.1186/gb-2005-6-8-227 [4] Baker LA, Allis CD, Wang GG. PHD fingers in human diseases:disorders arising from misinterpreting epigenetic marks[J]. Mutat Res, 2008, 647(1-2):3-12. doi: 10.1016/j.mrfmmm.2008.07.004 [5] Herz HM, Garruss A, Shilatifard A. SET for life:biochemical activities and biological functions of SET domain-containing proteins[J]. Trends Biochem Sci, 2013, 38(12):621-639. doi: 10.1016/j.tibs.2013.09.004 [6] Rona GB, Almeida DSG, Pinheiro AS, et al. The PWWP domain of the human oncogene WHSC1L1/NSD3 induces a metabolic shift toward fermentation[J]. Oncotarget, 2017, 8(33):54068-54081. doi: 10.18632/oncotarget.11253 [7] Kim SM, Kee HJ, Eom GH, et al. Characterization of a novel WHSC1-associated SET domain protein with H3K4 and H3K27 methyltransferase activity[J]. Biochem Biophys Res Commun, 2006, 345(1):318-323. doi: 10.1016/j.bbrc.2006.04.095 [8] Allali-Hassani A, Kuznetsova E, Hajian T, et al. A basic Post-SET extension of NSDs is essential for nucleosome binding in vitro[J]. J Biomol Screen, 2014, 19(6):928-935. doi: 10.1177/1087057114525854 [9] Li Y, Trojer P, Xu CF, et al. The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate[J]. J Biol Chem, 2009, 284(49):34283-34295. doi: 10.1074/jbc.M109.034462 [10] Wang Y, Reddy B, Thompson J, et al. Regulation of Set9-mediated H4K20 methylation by a PWWP domain protein[J]. Mol Cell, 2009, 33(4):428-437. doi: 10.1016/j.molcel.2009.02.002 [11] Wu H, Zeng H, Lam R, et al. Structural and histone binding ability characterizations of human PWWP domains[J]. PLoS One, 2011, 6(6):e18919. doi: 10.1371/journal.pone.0018919 [12] Rona GB, Almeida NP, Santos GC, et al. HNMR metabolomics reveals increased glutaminolysis upon overexpression of NSD3s or Pdp3 in Saccharomyces cerevisiae[J]. J Cell Biochem, 2019, 120(4):5377-5385. doi: 10.1002/jcb.27816 [13] Chang CF, Chu PC, Wu PY, et al. PHRF1 promotes genome integrity by modulating non-homologous end-joining[J]. Cell Death Dis, 2015, 6(4):e1716. doi: 10.1038/cddis.2015.81 [14] Shi X, Kachirskaia I, Walter KL, et al. Proteome-wide analysis in Saccharomyces cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36[J]. J Biol Chem, 2007, 282(4):2450-2455. doi: 10.1074/jbc.C600286200 [15] He C, Li F, Zhang J, et al. The methyltransferase NSD3 has chromatinbinding motifs, PHD5-C5HCH, that are distinct from other NSD (nuclear receptor SET domain) family members in their histone H3 recognition[J]. J Biol Chem, 2013, 288(7):4692-4703. doi: 10.1074/jbc.M112.426148 [16] Chen Y, McGee J, Chen X, et al. Identification of druggable cancer driver genes amplified across TCGA datasets[J]. PLoS One, 2014, 9(5):e98293. doi: 10.1371/journal.pone.0098293 [17] Yang ZQ, Liu G, Bollig-Fischer A, et al. Transforming properties of 8p11-12 amplified genes in human breast cancer[J]. Cancer Res, 2010, 70(21):8487-8497. doi: 10.1158/0008-5472.CAN-10-1013 [18] Rosati R, La Starza R, Veronese A, et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15)[J]. Blood, 2002, 99(10):3857-3860. doi: 10.1182/blood.V99.10.3857 [19] Taketani T, Taki T, Nakamura H, et al. NUP98-NSD3 fusion gene in radiation-associated myelodysplastic syndrome with t(8;11)(p11;p15) and expression pattern of NSD family genes[J]. Cancer Genet Cytogenet, 2009, 190(2):108-112. doi: 10.1016/j.cancergencyto.2008.12.008 [20] Zhang Q, Zeng L, Shen C, et al. Structural mechanism of transcriptional regulator nsd3 recognition by the ET domain of BRD4[J]. Structure, 2016, 24(7):1201-1208. doi: 10.1016/j.str.2016.04.019 [21] Chau NG, Ma C, Danga K, et al. An anatomical site and genetic-based prognostic model for patients with nuclear protein in testis (NUT) midline carcinoma:analysis of 124 patients[J]. JNCI Cancer Spectr, 2020, 4(2):pkz094. doi: 10.1093/jncics/pkz094 [22] French CA, Rahman S, Walsh EM, et al. NSD3-NUT fusion oncoprotein in NUT midline carcinoma:implications for a novel oncogenic mechanism[J]. Cancer Discov, 2014, 4(8):928-941. doi: 10.1158/2159-8290.CD-14-0014 [23] Kang D, Cho HS, Toyokawa G, et al. The histone methyltransferase WolfHirschhorn syndrome candidate 1-like 1(WHSC1L1) is involved in human carcinogenesis[J]. Genes Chromosomes Cancer, 2013, 52(1):126-139. http://europepmc.org/abstract/med/23011637 [24] Li Z, Ivanov AA, Su R, et al. The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies[J]. Nat Commun, 2017, 8(2):14356. [25] Liu Z, Piao L, Zhuang M, et al. Silencing of histone methyltransferase NSD3 reduces cell viability in osteosarcoma with induction of apoptosis[J]. Oncol Rep, 2017, 38(5):2796-2802. doi: 10.3892/or.2017.5936 [26] Saloura V, Vougiouklakis T, Zewde M, et al. WHSC1L1 drives cell cycle progression through transcriptional regulation of CDC6 and CDK2 in squamous cell carcinoma of the head and neck[J]. Oncotarget, 2016, 7(27):42527-42538. [27] Saloura V, Vougiouklakis T, Zewde M, et al. WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer[J]. Sci Rep, 2017, 7(1):40664. http://www.nature.com/articles/srep40664 [28] D'Afonseca V, Gonzalez G, Salazar M, et al. Computational analyses on genetic alterations in the NSD genes family and the implications for colorectal cancer development[J]. Ecancermedicalscience, 2020, 14(73):1001-1014. http://www.researchgate.net/publication/338610496_Computational_analyses_on_genetic_alterations_in_the_NSD_genes_family_and_the_implications_for_colorectal_cancer_development [29] Yi L, Yi L, Liu Q, et al. Downregulation of NSD3(WHSC1L1) inhibits cell proliferation and migration via ERK1/2 deactivation and decreasing CAPG expression in colorectal cancer cells[J]. Onco Targets Ther, 2019, 1(2):3933-3943. [30] Jones DH, Lin DI. Amplification of the NSD3-BRD4-CHD8 pathway in pelvic high-grade serous carcinomas of tubo-ovarian and endometrial origin[J]. Mol Clin Oncol, 2017, 7(2):301-307. [31] Zhang Y, Yan L, Yao W, et al. Integrated analysis of genetic abnormalities of the histone lysine methyltransferases in prostate cancer[J]. Med Sci Monit, 2019, 2(5):193-239. [32] Turner-Ivey B, Smith EL, Rutkovsky AC, et al. Development of mammary hyperplasia, dysplasia, and invasive ductal carcinoma in transgenic mice expressing the 8p11 amplicon oncogene NSD3[J]. Breast Cancer Res Treat, 2017, 164(2):349-358. doi: 10.1007/s10549-017-4258-9 [33] Shen C, Ipsaro JJ, Shi J, et al. NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler[J]. Mol Cell, 2015, 60(6):847-859. doi: 10.1016/j.molcel.2015.10.033 [34] French CA. NUT carcinoma:clinicopathologic features, pathogenesis, and treatment[J]. Pathol Int, 2018, 68(11):583-595. doi: 10.1111/pin.12727 [35] Yang Z, He N, Zhou Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression[J]. Mol Cell Biol, 2008, 28(3):967-976. doi: 10.1128/MCB.01020-07 [36] Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-dependent transcriptional elongation[J]. Cell, 2009, 138(1):129-145. doi: 10.1016/j.cell.2009.05.047 [37] Rahman S, Sowa ME, Ottinger M, et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3∇†[J]. Mol Cell Biol, 2011, 31(13):2641-2652. doi: 10.1128/MCB.01341-10 [38] Gonzalez-Pecchi V, Kwan AK, Doyle S, et al. NSD3S stabilizes MYC through hindering its interaction with FBXW7[J]. J Mol Cell Biol, 2020, 12(6):438-447. [39] Xiong J, Pecchi VG, Qui M, et al. Development of a time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the NSD3 and MYC interaction[J]. Assay Drug Dev Technol, 2018, 16(2):96-106. doi: 10.1089/adt.2017.835 [40] Böttcher J, Dilworth D, Reiser U, et al. Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3[J]. Nat Chem Biol, 2019, 15(8):822-829. doi: 10.1038/s41589-019-0310-x -
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