GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer.

IF 6.6 2区医学 Q1 Medicine Cellular Oncology Pub Date : 2022-06-01 Epub Date: 2022-05-03 DOI:10.1007/s13402-022-00675-8

Shilong Han, Chuanwu Cao, Rui Liu, YiFeng Yuan, Long Pan, Minjie Xu, Chao Hu, Xiaojun Zhang, Maoquan Li, Xiaoping Zhang

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引用次数: 5

Abstract

Purpose: GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role.

Methods: GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer.

Results: We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM.

Conclusion: Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.

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GAS41通过haa - z介导GEM的增殖和化学耐药。2和Notch1在胰腺癌中的表达

目的：GAS41是一种YEATS结构域蛋白，在非小细胞肺癌中与乙酰化组蛋白H3结合，促进H2A.Z的染色质沉积。GAS41 在胰腺癌中的作用尚不清楚。在此，我们旨在揭示这一作用：方法：使用 qRT-PCR、Western 印迹和免疫组化技术检测 GAS41 在胰腺癌组织和细胞系中的表达。方法：利用 qRTCR、Western 印迹和免疫组化技术检测了 GAS41 在胰腺癌组织和细胞系中的表达，并进行了 MTT、菌落形成、球形体形成和体内肿瘤发生试验，以评估胰腺癌细胞的增殖、肿瘤发生、干性和吉西他滨（GEM）耐药性。从机理上讲，我们采用了共免疫沉淀（co-immunoprecipitation，co-IP）和染色质免疫沉淀（chromatin immunoprecipitation，ChIP）实验来评估GAS41、H2A.Z.2和Notch1在胰腺癌中的作用：结果：我们发现 GAS41 在人类胰腺癌组织和细胞系中过表达，并且在获得 GEM 抗性后其表达增加。我们还发现 GAS41 在体外和体内上调 Notch 以及胰腺癌细胞的干性和 GEM 抗性。我们发现，GAS41与H2A.Z.2结合并激活Notch及其下游介质，从而调节干性和耐药性。研究发现，删除 GAS41 或 H2A.Z.2 可下调 Notch，并使胰腺癌细胞对 GEM 敏感：我们的数据表明，GAS41通过H2A.Z.2和Notch1介导了胰腺癌细胞的增殖和对GEM的耐药性。

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来源期刊

Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

10.40

自引率

1.50%

发文量

审稿时长

16 weeks

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.