NSD3, a Member of Nuclear Receptor-binding SET Domain Family, is a Potential Prognostic Biomarker for Pancreatic Cancer

Overview

Journal Cancer Med

Specialty Oncology

Date 2023 Apr 16

PMID 37062069

Authors

Qunli Xiong

Ying Zhou

Su Zhang

Yaguang Zhang

Yongfeng Xu

Yang Yang

Congya Zhou

Zhu Zeng

Junhong Han

Qing Zhu

Affiliations

Soon will be listed here.

Abstract

Background: Members of the nuclear receptor-binding SET domain (NSD) family of histone H3 lysine 36 methyltransferases comprise NSD1, NSD2 (MMSET/WHSC1), and NSD3 (Wolf-Hirschhorn syndrome candidate 1-like 1, WHSC1L1). While the expression of NSD genes is essential to normal biological processes and cancer, knowledge of their expression levels to prognosticate in cancer remains unclear.

Methods: We analyzed the expression patterns for NSD family genes across multiple cancer types and examined their association with clinical features and patient survival profiles. Next, we explored the association between NSD3 expression and described features of the tumor microenvironment (TME) in PAAD, a severe type of pancreatic cancer. In particular, we correlated promoter methylation levels for NSD3 with patient outcomes in PAAD. Finally, we explored the putative oncogenic roles for NSD3 using a series of experiments with pancreatic cancer cells.

Results: We report that the expression of NSD family members is correlated with clinical prognosis across multiple types of cancers. Also, we demonstrate that NSD3 variants are most prevalent among NSD genes across cancers we analyzed. Notably, when compared with NSD1 and NSD2, we find that NSD3 is prominently expressed, and its expression is significantly linked with clinical outcome in pancreatic cancer. Furthermore, NSD3 is frequently amplified, exhibits low promoter methylation, and is correlated with immune cell infiltration and enhanced proliferation of pancreatic cancer. Finally, we demonstrate that knockdown of NSD3 alters H3K36me2 methylation, downstream gene expression and EGFR/ERK signaling in pancreatic cancer cells.

Conclusions: We find that expression levels, the presence of genetic variants of NSD family genes, as well as their promoter methylation are correlated with clinical outcomes in cancer, including pancreatic cancer. Our in vitro experiments suggest that NSD3 may be relevant to gene expression regulation and growth factor signaling in pancreatic cancer.

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References

Saloura V, Vougiouklakis T, Zewde M, Deng X, Kiyotani K, Park J . WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer. Sci Rep. 2017; 7:40664. PMC: 5244396. DOI: 10.1038/srep40664. View

Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz R . A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009; 460(7252):287-91. DOI: 10.1038/nature08086. View

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

Li W, Tian W, Yuan G, Deng P, Sengupta D, Cheng Z . Molecular basis of nucleosomal H3K36 methylation by NSD methyltransferases. Nature. 2020; 590(7846):498-503. PMC: 7889650. DOI: 10.1038/s41586-020-03069-8. View

Vermeulen M, Eberl H, Matarese F, Marks H, Denissov S, Butter F . Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell. 2010; 142(6):967-80. DOI: 10.1016/j.cell.2010.08.020. View

Tang Z, Kang B, Li C, Chen T, Zhang Z . GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019; 47(W1):W556-W560. PMC: 6602440. DOI: 10.1093/nar/gkz430. View

Zuber J, Shi J, Wang E, Rappaport A, Herrmann H, Sison E . RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011; 478(7370):524-8. PMC: 3328300. DOI: 10.1038/nature10334. View

Jeong G, Park M, Choi H, An H, Park Y, Choi H . NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression. Cancer Res. 2020; 81(1):77-90. DOI: 10.1158/0008-5472.CAN-20-0360. View

Wang Z, Hulsurkar M, Zhuo L, Xu J, Yang H, Naderinezhad S . CKB inhibits epithelial-mesenchymal transition and prostate cancer progression by sequestering and inhibiting AKT activation. Neoplasia. 2021; 23(11):1147-1165. PMC: 8551525. DOI: 10.1016/j.neo.2021.09.005. View

10.

Topper M, Vaz M, Marrone K, Brahmer J, Baylin S . The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol. 2019; 17(2):75-90. PMC: 7254932. DOI: 10.1038/s41571-019-0266-5. View

11.

Zhou P, Wu L, Wu K, Jiang W, Li J, Zhou L . Overexpression of MMSET is correlation with poor prognosis in hepatocellular carcinoma. Pathol Oncol Res. 2012; 19(2):303-9. DOI: 10.1007/s12253-012-9583-z. View

12.

Yang Y, Gao L, Weng N, Li J, Liu J, Zhou Y . Identification of Novel Molecular Therapeutic Targets and Their Potential Prognostic Biomarkers Among Kinesin Superfamily of Proteins in Pancreatic Ductal Adenocarcinoma. Front Oncol. 2021; 11:708900. PMC: 8454465. DOI: 10.3389/fonc.2021.708900. View

13.

Shah M, Martinez-Garcia E, Phillip J, Chambliss A, Popovic R, Ezponda T . MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents. Oncogene. 2016; 35(45):5905-5915. PMC: 6071667. DOI: 10.1038/onc.2016.116. View

14.

Vougiouklakis T, Hamamoto R, Nakamura Y, Saloura V . The NSD family of protein methyltransferases in human cancer. Epigenomics. 2015; 7(5):863-74. DOI: 10.2217/epi.15.32. View

15.

Bennett R, Swaroop A, Troche C, Licht J . The Role of Nuclear Receptor-Binding SET Domain Family Histone Lysine Methyltransferases in Cancer. Cold Spring Harb Perspect Med. 2017; 7(6). PMC: 5453381. DOI: 10.1101/cshperspect.a026708. View

16.

Zhu J, Liu Z, Liang X, Wang L, Wu D, Mao W . A Pan-Cancer Study of KMT2 Family as Therapeutic Targets in Cancer. J Oncol. 2022; 2022:3982226. PMC: 8766195. DOI: 10.1155/2022/3982226. View

17.

Kirtonia A, Pandey A, Ramachandran B, Mishra D, Dawson D, Sethi G . Overexpression of laminin-5 gamma-2 promotes tumorigenesis of pancreatic ductal adenocarcinoma through EGFR/ERK1/2/AKT/mTOR cascade. Cell Mol Life Sci. 2022; 79(7):362. PMC: 11073089. DOI: 10.1007/s00018-022-04392-1. View

18.

Wang C, Wang Q, Xu X, Xie B, Zhao Y, Li N . The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3. J Exp Med. 2017; 214(12):3597-3610. PMC: 5716042. DOI: 10.1084/jem.20170856. View

19.

Zhang X, Li Y, Ji J, Wang X, Zhang M, Li X . Gadd45g initiates embryonic stem cell differentiation and inhibits breast cell carcinogenesis. Cell Death Discov. 2021; 7(1):271. PMC: 8487429. DOI: 10.1038/s41420-021-00667-x. View

20.

Lucio-Eterovic A, Singh M, Gardner J, Veerappan C, Rice J, Carpenter P . Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function. Proc Natl Acad Sci U S A. 2010; 107(39):16952-7. PMC: 2947892. DOI: 10.1073/pnas.1002653107. View