Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy
| Autor: | Yunshan Wang, Ji-Eun Kim, Roshane Francis, Shaheed W Hakim, Jung-Eun Kim, Housheng Hansen He, Jieun Seo, Tae-Hee Kim, Haiyang Guo, Adrian Kwan Ho Loe, Lutao Du |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
ARID1A Carcinogenesis Immunology Biology medicine.disease_cause Chromatin remodeling Article Loss of heterozygosity 03 medical and health sciences Mice 0302 clinical medicine Stomach Neoplasms medicine Immunology and Allergy Animals Epigenetics Solid Tumors Cell Proliferation Sequence Deletion Homozygote Stomach Cancer Heterozygote advantage medicine.disease 3. Good health DNA-Binding Proteins Gene Expression Regulation Neoplastic 030104 developmental biology Tumor progression 030220 oncology & carcinogenesis Cancer research Tumor Suppressor Protein p53 Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Loe et al. demonstrate dosage-dependent roles of Arid1a, whereby the loss of its single copy promotes tumor progression, but tumor cells lacking both copies exhibit a survival disadvantage. This finding leads to a novel combined targeting approach for the effective inhibition of Arid1a heterozygous tumor cell growth. Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC. Graphical Abstract |
| Databáze: | OpenAIRE |
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