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

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.

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

“…In breast cancer, increased expression of NSD3 correlated with a decrease CD8+ T cells and increased PD-L1 gene [65], in agreement with Xu et al in lung cancer. In contrast, in PAAD, through bioinformatic studies, upregulation of NSD3 correlated with increased immune infiltration, specifically macrophages, B cells, neutrophils, CD8+ T cells and dendritic cells [47]. Taken together, there is evidence linking the role of NSD3 in IFN response and immune modulation, however, further studies are needed to accurately state the function.…”

“…A study in colorectal cancer (CRC) cells showed that overexpression of NSD3 increased phosphorylation of ERK leading to an enhancement of proliferation and migration of CRC cells [60]. Xiong et al, on pancreatic cancer cells, also found a correlation on a decrease of EGFR/ERK pathway activation with NSD3 knockdown [47].…”

“…Xiong et al describes that exist a variety of NDS3 missense mutations and T419Pfs*8/Nfs*28/N mutations were detected in four cases of Stomach adenocarcinoma (STAD), two cases of colon adenocarcinoma (COAD) and single cases of breast invasive carcinoma (BRCA) and pancreatic adenocarcinoma (PAAD). Likewise, nonsense mutations of NSD3, such as, E1181K and T2342A, enhance the growth of cancer cells and xenograft tumors by disrupting an autoinhibitory loop of the NSD3 protein product, thereby increasing its enzymatic function [47,48]. More studies in relation to the mutations found in NSD3 are necessary to identify the significance of those mutations on cancer progression.…”

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

“…Xiong et al described a variety of NDS3 missense mutations and T419Pfs*8/Nfs*28/N mutations in four cases of stomach adenocarcinoma (STAD), two cases of colon adenocarcinoma (COAD) and single cases of breast invasive carcinoma (BRCA) and pancreatic adenocarcinoma (PAAD). Likewise, nonsense mutations in NSD3, such as, E1181K and T2342A, enhance the growth of cancer cells and xenograft tumors by disrupting an autoinhibitory loop in the NSD3 protein, thereby increasing enzymatic activity [47,48]. More studies regarding the mutations found in NSD3 are necessary to identify the significance of these mutations on cancer progression.…”

“…A study in colorectal cancer (CRC) cells showed that overexpression of NSD3 increased phosphorylation of ERK, leading to enhanced proliferation and migration of CRC cells [60]. Xiong et al, in pancreatic cancer cells, also found a correlation between decreased EGFR/ERK pathway activation and NSD3 knockdown [47].…”