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[Hospital News] Paper Published by Guo Haiyang and His Team in JEM to Reveal the Effect of Chromatin Remodeling Protein on Gastric Tumorigenesis

Release time:2021-04-19     Clicks:0

Guo Haiyang and his team from the Second Hospital of Shandong University Laboratory Medicine Center have recently published a new research paper titled "Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy" in the Journal of Experimental Medicine (Area 1 of Chinese Academy of Sciences, IF=11.743), revealing the influence of genomic epigenetic modification mediated by deletion of chromatin remodelers Arid1a on gastric tumorigenesis. This paper is the result of the collaboration between the Laboratory Medical Center affiliated to the Second Hospital of Shandong University and the team of Tae-Hee Kim from the Hospital for Sick Children (SickKids) of the University of Toronto. Prof. Tae-Hee Kim and Researcher Guo Haiyang are co-corresponding authors.

It is reported that gastric cancer is the third most lethal malignancy worldwide, accounting for about 8% of all cancer deaths each year. A prominent feature of the gastric cancer genome is the high mutation rate of chromatin modifier genes. For example, the mutation rates of ARID1A and ARID1B, components of the BAF chromatin remodeling complex, are 14-31% and 9% respectively in gastric cancer. The BAF complex mobilizes nucleosomes in an ATP-dependent manner and extensively alters the histone modification of the genome. The mutation of components of the complex plays an important role in the occurrence of a variety of tumors. In terms of gastric cancer, recent clinical studies have found that deletion of ARID1A is associated with poor prognosis and lymph node metastasis in patients, and researches on some cell models have also shown that low expression of ARID1A can promote the growth and migration of gastric cancer cells. However, the role and specific mechanism of ARID1A in gastric tumorigenesis in animal models are still unclear.

1副本

Guo and his team furthered constructed the mouse models with heterozygous deletion of ARID1A gene (Atp4bCre;Rosa26NICD;Arid1aflox/+) and homozygous deletion (Atp4bCre;Rosa26NICD;Arid1aflox/flox) based on the mouse models with  Notch signaling activation in gastric cancer (Atp4bCre;Rosa26NICD). Compared with gastric cancer with complete ARID1A gene, gastric cancer with heterozygous deletion of ARID1A showed stronger proliferation ability. However, the indicators of malignancy of gastric cancer with homozygous deletion of ARID1A gene were significantly lower than those with heterozygous deletion, which was quite unexpected. Immunofluorescence staining showed that although homozygous knockout of ARID1A gene showed high efficiency in the early stage, ARID1A positive gastric cancer cells gradually replaced ARID1A negative gastric cancer cells through proliferation over time. To explore the mechanism of the dosage-dependent effect of ARID1A gene on gastric tumorigenesis, the team performed RNA-Seq, H3K27ac and H3K4me3 ChIP-Seq tests on rats with normal gastric tissues, tissues with ARID1A gene-integrity gastric cancer, gastric cancer tissues with heterozygous deletion of ARID1A and early-stage gastric cancer tissues with homozygous deletion of ARID1A respectively, as well as conducting single cell RNA-Seq on Atp4bCre;Rosa26NICD;Arid1aflox/flox. Overall analysis and in vivo validation showed that the heterozygous deletion of ARID1A gene resulted in extensive H3K27ac modifier loss in the gastric cancer genome, which was concentrated in the enhancer region of the important tumor suppressor pathway TP53 and the apoptosis pathway. As a result, the expression of apoptosis-related genes in gastric cancer with heterozygous ARID1A deletion was inhibited and the apoptosis rate at the late stage was significantly decreased. However, in the case of gastric cancer with homozygous deletion of ARID1A, part of the enhancer regions of TP53/ apoptotic-related genes were re-modified by H3K27ac, resulting in an increased apoptosis rate compared with gastric cancer with heterozygous deletion.

 Based on the finding that homozygous deletion of ARID1A reduced the adaptation of gastric cancer cells, the team proposed that deep inhibition of BAF complex activity could effectively kill gastric cancer cells containing partial expression of ARID1A, and verified the killing effect of TP064, a BAF complex inhibitor, on organ cells in the case of gastric cancer with heterozygous deletion of ARID1A. Furthermore, based on the finding that TP53 pathway is inhibited in gastric cancer with heterozygous deletion of ARID1A, the team came up with the idea that activation of TP53 pathway activity could further kill gastric cancer with heterozygous deletion of ARID1A. In addition, they had proved that the combination of TP064, and TP53 agonist, Nutlin-3 has a significant synergistic killing effect on organ cells in gastric cancer with heterozygous deletion of ARID1A.

 This study not only introduced the unique dosage-dependent effect of ARID1A in gastric tumorigenesis, but also revealed the vulnerability of gastric cancer with heterozygous deletion of ARID1A, which has important potential clinical values in the application of the combination therapy to inhibit BAF complex and activate the TP53 pathway. The research work was supported by the Key Research and Development Program of the Ministry of Science and Technology and the Taishan Scholars Project of Shandong Province.

 The research team led by Guo Haiyang has been working on the study of tumor epigenomics, has systematically analyzed and verified a series of long non-coding RNAs related to the risk of prostate cancer, and revealed the epigenetic mechanism of such transcription factors as ONECUT2、SOX2 in the occurrence and progression of prostate cancer and gastric cancer. The research accomplishments have been published in Nature Genetics(2016), Nature Communications(2019)、Science Advances(2019), with Guo Haiyang as the first/corresponding author. Guo Haiyang’s research team has been recruiting postdoctoral or full-time staff major in the field of molecular biology or bioinformatics. For more information, please refer to:

http://muchong.com/t-14505472-1

http://talent.sciencenet.cn/index.php?s=/Info/index/id/19955

论文链接:Find more about the paper:

https://rupress.org/jem/article-abstract/218/6/e20200219/211950/Uncovering-the-dosage-dependent-roles-of-Arid1a-in?redirectedFrom=fulltext

{Author: Du Lutao   Source: Scientific Research Department Edited by: Publicity Department/News Center}


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