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Abstract：
Although histone H3K4 methyltransferase SETD1A is overexpressed in various cancer types, the molecular mechanism underlying its overexpression and its target genes in pancreatic ductal adenocarcinoma (PDAC) remain unclarified. We conducted immunohistochemical staining for SETD1A in 105 human PDAC specimens to assess the relationship between SETD1A overexpression and clinicopathological features. The function and target genes of SETD1A were investigated using human pancreatic cancer cell lines. SETD1A expression was upregulated in 51.4% of patients with PDAC and was an independent prognostic factor associated with shorter disease-free survival after resection (p < 0.05). Knockdown and overexpression of SETD1A showed that SETD1A plays a crucial role in increasing the proliferation and motility of PDAC cells. SETD1A overexpression increased tumorigenicity. RNA sequencing of SETD1A-knockdown cells revealed downregulation of RUVBL1, an oncogenic protein ATP-dependent DNA helicase gene. ChIP analysis revealed that SETD1A binds to the RUVBL1 promoter region, resulting in increased H3K4me3 levels. Knockdown of RUVBL1 showed inhibition of cell proliferation, migration, and invasion of PDAC cells, which are similar biological effects to SETD1A knockdown. High expression of both SETD1A and RUVBL1 was an independent prognostic factor not only for disease-free survival but also for overall survival (p < 0.05). In conclusion, we identified RUVBL1 as a novel downstream target gene of the SETD1A-H3K4me3 pathway. Co-expression of SETD1A and RUVBL1 is an important factor for predicting the prognosis of patients with PDAC.
摘要：
尽管组蛋白H3K4甲基转移酶SETD1A在各种癌症类型中过表达，其在胰腺导管腺癌(PDAC)中过表达及其靶基因的分子机制尚不清楚.我们在105例人PDAC标本中对SETD1A进行了免疫组织化学染色，以评估SETD1A过表达与临床病理特征之间的关系。使用人胰腺癌细胞系研究SETD1A的功能和靶基因。51.4%的PDAC患者中SETD1A表达上调，是与切除后无病生存期缩短相关的独立预后因素(p<0.05)。SETD1A的敲低和过表达表明SETD1A在增加PDAC细胞的增殖和运动中起着至关重要的作用。SETD1A过表达增加了致瘤性。SETD1A敲低细胞的RNA测序显示RUVBL1下调，RUVBL1是一种致癌蛋白ATP依赖性DNA解旋酶基因。ChIP分析显示SETD1A与RUVBL1启动子区结合,导致H3K4me3水平升高。RUVBL1的敲低显示细胞增殖的抑制，迁移,和PDAC细胞的侵袭，与SETD1A敲低相似的生物学效应。SETD1A和RUVBL1的高表达不仅是无病生存率而且是总生存率的独立预后因素(p<0.05)。总之,我们将RUVBL1鉴定为SETD1A-H3K4me3通路的一个新的下游靶基因。SETD1A和RUVBL1的共表达是预测PDAC患者预后的重要因素。
