Ras-ERK1/2 信号通路通过 PCAF 调节 H3K9ac 促进胰腺癌的发展。

The Ras-ERK1/2 signaling pathway regulates H3K9ac through PCAF to promote the development of pancreatic cancer.

机构信息

Department of Pathology, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China.

Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.

出版信息

Life Sci. 2020 Sep 1;256:117936. doi: 10.1016/j.lfs.2020.117936. Epub 2020 Jun 9.

DOI:10.1016/j.lfs.2020.117936

PMID:32531376

Abstract

AIMS

The regulation of the Ras-ERK pathway is the crucial point in pancreatic carcinogenesis, and the Ras kinase is an essential regulatory upstream signal molecule of the ERK1/2 pathway. H3K9ac is a vital histone modification, but its specific role in pancreatic cancer remains unclear. This research aims to study whether the modification level of H3K9ac can regulate the characteristic phenotype of the pancreatic cancer cells by affecting the downstream expression, proliferation, migration, and other related genes.

MAIN METHODS

The Ras were used to transfect pancreatic cancer cells, and the levels of phosphorylated ERK1/2 and H3K9ac were detected by western blotting. The colony formation assay, transwell assay, and chromatin immunoprecipitation assay were used to study cell viability, migration, and the downstream genes of the ERK1/2 pathway.

KEY FINDINGS

The results showed that Ras ERK1/2 reduced H3K9ac expression in ASPC-1 cells, and H3K9ac significantly repressed the viability of cells, colony formation, and ASPC-1 cell movement induced by Ras ERK1/2. Besides, HDAC1 silencing increased H3K9ac expression, and changed the effect of Ras ERK1/2 on ASPC-1 cells proliferation, its movement, and mRNAs of ERK1/2 downstream genes. Moreover, Ras ERK1/2 inhibited H3K9ac expression by the degradation of PCAF via MDM2.

SIGNIFICANCE

Ras ERK1/2 promotes pancreatic carcinogenesis cell movement, through down-regulating H3K9ac via MDM2 mediated PCAF degradation.

摘要

目的

Ras-ERK 通路的调节是胰腺发生癌变的关键点，而 Ras 激酶是 ERK1/2 通路的必需调节上游信号分子。H3K9ac 是一种重要的组蛋白修饰，但它在胰腺癌中的具体作用尚不清楚。本研究旨在通过影响下游表达、增殖、迁移和其他相关基因，研究 H3K9ac 的修饰水平是否可以通过调节胰腺癌细胞的特征表型来调节。

主要方法

用 Ras 转染胰腺癌细胞，通过 Western blot 检测磷酸化 ERK1/2 和 H3K9ac 的水平。通过集落形成试验、Transwell 试验和染色质免疫沉淀试验研究细胞活力、迁移和 ERK1/2 通路的下游基因。

主要发现

结果表明，Ras ERK1/2 降低了 ASPC-1 细胞中的 H3K9ac 表达，H3K9ac 显著抑制了 Ras ERK1/2 诱导的细胞活力、集落形成和 ASPC-1 细胞迁移。此外，HDAC1 沉默增加了 H3K9ac 的表达，并改变了 Ras ERK1/2 对 ASPC-1 细胞增殖、运动和 ERK1/2 下游基因 mRNA 的影响。此外，Ras ERK1/2 通过 MDM2 介导的 PCAF 降解抑制 H3K9ac 表达。