Multi-omics approaches identify SF3B3 and SIRT3 as candidate autophagic regulators and druggable targets in invasive breast carcinoma
| Autor: | Yang An, Jin Zhang, Xiaoxi Zeng, Yuqian Zhao, Shouyue Zhang, Ziyi Qin, Heng Xu, Bo Liu |
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| Rok vydání: | 2021 |
| Předmět: |
Druggable target
Programmed cell death Candidate gene CNA copy number alteration Regulator Druggability RM1-950 Biology Autophagic regulator TNBC triple-negative breast cancer SIRT3 03 medical and health sciences 0302 clinical medicine Breast cancer BRCA invasive breast carcinoma ATG autophagy-related gene GO Gene Ontology Gene expression medicine General Pharmacology Toxicology and Pharmaceutics Migration SNF similarity network fusion 030304 developmental biology 0303 health sciences LASSO least absolute shrinkage and selection operator Autophagy SF3B3 medicine.disease Multi-omics approach PFS progression-free survival Invasive breast carcinoma MET DNA methylation Anti-proliferation EXP gene expression 030220 oncology & carcinogenesis DNA methylation Cancer research TCGA The Cancer Genome Atlas Original Article Therapeutics. Pharmacology |
| Zdroj: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 11, Iss 5, Pp 1227-1245 (2021) |
| ISSN: | 2211-3835 |
| DOI: | 10.1016/j.apsb.2020.12.013 |
| Popis: | Autophagy is a critical cellular homeostatic mechanism, and its dysfunction is linked to invasive breast carcinoma (BRCA). Recently, several omics methods have been applied to explore autophagic regulators in BRCA; however, more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered. Thus, we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA, including gene expression (EXP), DNA methylation (MET) and copy number alterations (CNAs) from The Cancer Genome Atlas (TCGA). Newly identified candidate genes, such as SF3B3, TRAPPC10, SIRT3, MTERFD1, and FBXO5, were confirmed to be involved in the positive or negative regulation of autophagy in BRCA. SF3B3 was identified firstly as a negative autophagic regulator, and siRNA/shRNA-SF3B3 were shown to induce autophagy-associated cell death in in vitro and in vivo breast cancer models. Moreover, a novel small-molecule activator of SIRT3, 1-methylbenzylamino amiodarone, was discovered to induce autophagy in vitro and in vivo. Together, these results provide multi-omics approaches to identify some key candidate autophagic regulators, such as the negative regulator SF3B3 and positive regulator SIRT3 in BRCA, and highlight SF3B3 and SIRT3 as new druggable targets that could be used to fill the gap between autophagy and cancer drug development. Graphical abstract This study provides multi-omics approaches to identify some key candidate autophagic regulators, such as the negative regulator SF3B3 and positive regulator SIRT3 in invasive breast carcinoma, and highlight them as new druggable targets.Image 1 |
| Databáze: | OpenAIRE |
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