NSD3, a member of nuclear receptor-binding SET domain family, is a potential prognostic biomarker for pancreatic cancer

Sep 24, 2026

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Background: NSD family members are H3K36 methyltransferases, but how NSD gene expression levels can be used to predict outcomes in cancer remains unclear. Methods: Expression across cancer types was analyzed for links to clinical features and survival, then NSD3 was further studied in PAAD using tumor microenvironment data and promoter methylation correlations. Results: NSD3 shows prominent expression in pancreatic cancer, frequent amplification, low promoter methylation, immune infiltration association, and altered H3K36me2 signaling. Conclusions: NSD3 expression, variants, and promoter methylation correlate with cancer outcomes, suggesting relevance to gene regulation and growth factor signaling.

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DOI: 10. 1002/cam4 .5774 RESEAR CH ARTICLE NSD3, a member of nuclear receptor-binding SET domain family, is a potential prognostic biomarker for pancreatic cancer Qunli Xiong1,2 | Ying Zhou1,2 | Su Zhang2 | Yaguang Zhang2 | Yongfeng Xu1,2 | Yang Yang1 | Congya Zhou3 | Zhu Zeng1 | Junhong Han2 | Qing Zhu1,2 1Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China 2Research Laboratory of Cancer Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China 3Department of Radiation Oncology, Shaanxi Provincial People's Hospital, Xi'an, China Correspondence Junhong Han and Qing Zhu, Research Laboratory of Cancer Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. [Email:](Email: hjunhong@scu.edu.cn and)[ hjunhong@scu.edu.cn](Email: hjunhong@scu.edu.cn and)[ and](Email: hjunhong@scu.edu.cn and)[ ](Email: hjunhong@scu.edu.cn and)[newzhuqing1972@163.com](newzhuqing1972@163.com) Funding information Qing Zhu, Grant/Award Number: 2019YFS0042 and ZYJC21042; Yaguang Zhang, Grant/Award Number: 18HXBH068 and 2022NSFSC1424 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 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. suggest that NSD3 may be relevant to gene expression regulation and growth factor signaling in pancreatic cancer. KEYWORDS cell proliferation, immune infiltration, NSD3, nuclear receptor-binding SET domain, pancreatic cancer, prognosis biomarker 1 | INTRODUCTION Cancer is the leading cause of death around the worldwide. In 2020, it was estimated that over 19.3 million peopl

FAQs

What was the main research focus of the study?

The study investigated whether NSD family gene expression, especially NSD3, can serve as a prognostic biomarker and how NSD3 relates to clinical features and patient survival in pancreatic cancer.

How was NSD3 associated with patient prognosis in pancreatic cancer?

NSD3 expression was significantly linked with clinical outcomes in PAAD, and promoter methylation levels for NSD3 were correlated with patient outcomes.

What experimental findings connected NSD3 to biological mechanisms in pancreatic cancer cells?

Knockdown of NSD3 altered H3K36me2 methylation, downstream gene expression, and EGFR/ERK signaling in pancreatic cancer cells.

Sep 24, 2026

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