背景:组蛋白H3赖氨酸36甲基转移酶的核受体结合SET域(NSD)家族成员包括NSD1,NSD2(MMSET/WHSC1),和NSD3(Wolf-Hirschhorn综合征候选1-like1,WHSC1L1)。虽然NSD基因的表达对正常生物过程和癌症至关重要,他们的表达水平对癌症预后的了解尚不清楚。
方法:我们分析了多种癌症类型中NSD家族基因的表达模式,并检查了它们与临床特征和患者生存状况的关联。接下来,我们探索了NSD3表达与PAAD中肿瘤微环境(TME)的描述特征之间的关联,一种严重的胰腺癌.特别是,我们将NSD3启动子甲基化水平与PAAD患者预后相关.最后,我们使用一系列胰腺癌细胞实验,探索了NSD3的推定致癌作用.
结果:我们报道NSD家族成员的表达与多种癌症的临床预后相关。此外,我们证明NSD3变异在我们分析的所有癌症中的NSD基因中最为普遍.值得注意的是,当与NSD1和NSD2相比时,我们发现NSD3被突出地表达,其表达与胰腺癌的临床预后显著相关。此外,NSD3经常被扩增,表现出低启动子甲基化,并与胰腺癌的免疫细胞浸润和增殖增强有关。最后,我们证明NSD3的敲低改变了H3K36me2甲基化,胰腺癌细胞的下游基因表达和EGFR/ERK信号传导。
结论:我们发现表达水平,NSD家族基因的遗传变异的存在,以及它们的启动子甲基化与癌症的临床结果相关,包括胰腺癌.我们的体外实验表明,NSD3可能与胰腺癌的基因表达调控和生长因子信号传导有关。
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.
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.
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.
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.