Constitutive ERK1/2 activation has been frequently observed in pancreatic adenocarcinoma (PDAC). How ERK1/2 activation status been potentiated and maintained by epigenetic mechanisms has seldom been discussed in PDAC. In this study, we first examined the expression status of p-ERK1/2 in PDAC tissues by immunohistochemical staining and then screened possible epigenetic factors that displayed different expression status between p-ERK1/2 high and low groups by RNA profiling, and found that SETD8 displayed an increased expressional pattern in p-ERK1/2^high patient group. Then the impact of SETD8 on the proliferation of PDAC cells were investigated on the basis of gain or loss-of-function assays. RNA sequencing assays were performed to screen potential SETD8 downstream targets that contribute to ERK1/2 activation. Mass spectrometry and transcriptional analysis, including dual-luciferase assay and chromatin immunoprecipitation assay (ChIP), were used to explore the molecular mechanisms that governing SETD8-mediated ERK1/2 activation. In vitro cell line studies and in vivo xenograft mouse model studies indicated that SETD8 promoted cell proliferation and increased tumor formation capacity of PDAC cell lines. Mechanism explorations uncovered that SETD8 suppressed the expression of DUSP10, which was responsible for dephosphorylation of ERK1/2. Mass spectrometry and transcriptional analysis results demonstrated that STAT3 interacted with SETD8 and recruited SETD8 to the promoter region of DUSP10, leading to epigenetic silencing of DUSP10 and the resultant activation of ERK1/2. In conclusion, SETD8 interacts with STAT3 on DUSP10 promoter region and epigenetically silences DUSP10 expression. Decreased DUSP10 expression in PDAC potentiates activation of ERK1/2 phosphorylation, resulting in unfavorable prognosis of PDAC.

在胰腺腺癌（PDAC）中经常观察到ERK1 / 2的组成性激活。在PDAC中很少讨论如何通过表观遗传机制增强和维持ERK1 / 2激活状态。在这项研究中，我们首先通过免疫组织化学染色检查了PDAC组织中p -ERK1 / 2的表达状态，然后通过RNA分析筛选了可能显示p -ERK1 / 2高和低组之间不同表达状态的表观遗传因子，发现SETD8在p -ERK1 / 2^高处显示出增加的表达方式病人组。然后，基于获得或丧失功能的检测方法，研究了SETD8对PDAC细胞增殖的影响。进行RNA测序分析以筛选有助于ERK1 / 2激活的潜在SETD8下游靶标。质谱和转录分析，包括双荧光素酶测定和染色质免疫沉淀测定（ChIP），用于探索控制SETD8介导的ERK1 / 2活化的分子机制。体外细胞系研究和体内异种移植小鼠模型研究表明，SETD8促进细胞增殖并增加PDAC细胞系的肿瘤形成能力。机制探索发现SETD8抑制DUSP10的表达，而DUSP10负责ERK1 / 2的去磷酸化。质谱和转录分析结果表明，STAT3与SETD8相互作用并将SETD8募集到DUSP10的启动子区域，导致DUSP10的表观遗传沉默和由此导致的ERK1 / 2激活。总之，SETD8与DUSP10启动子区域的STAT3相互作用，并在表观遗传上沉默DUSP10表达。PDAC中DUSP10表达的降低会增强ERK1 / 2磷酸化的激活，导致PDAC的预后不良。