A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer
| العنوان: | A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer |
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| المؤلفون: | Qun Liu, Heshu Liu, Xuying Huang, Xiaona Fan, Zeru Xiao, Rui Yan, Jiannan Yao, Guanyu An, Yang Ge, Jinwei Miao, Jian Liu |
| المصدر: | Cancer Gene Therapy. 30:192-208 |
| بيانات النشر: | Springer Science and Business Media LLC, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Molecular Medicine, Molecular Biology |
| الوصف: | The chromatin-modifying enzyme ATAD2 confers oncogenic competence and proliferative advantage in malignances. We previously identified ATAD2 as a marker and driver of cell proliferation in ovarian cancer (OC); however, the mechanisms whereby ATAD2 is regulated and involved in cell proliferation are still unclear. Here, we disclose that ATAD2 displays a classical G2/M gene signature, functioning to facilitate mitotic progression. ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. ChIP-seq data analyses demonstrated that DREAM and MYBL2-MuvB (MMB), two switchable MuvB-based complexes, bind the CHR elements in the ATAD2 promoter, representing a typical feature and principle mechanism of the periodic regulation of G2/M genes. As a downstream target of MYBL2, ATAD2 deletion significantly impaired MYBL2-driven cell proliferation. Intriguingly, ATAD2 silencing also fed back to destabilize the MYBL2 protein. The significant coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels highlights the existence of the MYBL2-ATAD2 signaling in OC patients. This signaling is activated during tumorigenesis and correlated with TP53 mutation, and its hyperactivation was found especially in high-grade serous and drug-resistant OCs. Disrupting this signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model, while pharmacologically targeting this signaling with an ATAD2 inhibitor demonstrated high therapeutic efficacy in both drug-sensitive and drug-resistant OC cells. Collectively, we identified a novel MYBL2-ATAD2 proliferative signaling axis and highlighted its potential application in developing new therapeutic strategies, especially for high-grade serous and drug-resistant OCs. |
| تدمد: | 1476-5500 0929-1903 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::316c27fd9c8b35dfdfd8fa0eb3010bab https://doi.org/10.1038/s41417-022-00538-2 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....316c27fd9c8b35dfdfd8fa0eb3010bab |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765500 09291903 |
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