Loss of SIRT4 promotes the self-renewal of Breast Cancer Stem Cells
Autor: | Yunshan Wang, Yuli Wang, Yidan Ren, Fang Wang, Peilong Li, Peng Meng, Chuanxin Wang, Juan Li, Qinlian Jiao, Xiaoyan Liu, Lutao Du |
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Rok vydání: | 2020 |
Předmět: |
cancer stemness
0301 basic medicine Carcinogenesis Glutamine Medicine (miscellaneous) Mice 0302 clinical medicine Sirtuin 1 glutamine metabolism Homeostasis Sirtuins Cell Self Renewal skin and connective tissue diseases Pharmacology Toxicology and Pharmaceutics (miscellaneous) Mice Knockout Mice Inbred BALB C Gene knockdown biology Mitochondria 030220 oncology & carcinogenesis Sirtuin MCF-7 Cells Neoplastic Stem Cells Female Stem cell Research Paper Tumor suppressor gene Mice Nude Breast Neoplasms Cell Line Mitochondrial Proteins SIRT4 03 medical and health sciences SIRT1 breast cancer Breast cancer Cell Line Tumor medicine Animals Humans Progenitor cell Mammary Glands Human Clonogenic assay Cancer Epithelial Cells medicine.disease HEK293 Cells 030104 developmental biology biology.protein Cancer research |
Zdroj: | Theranostics |
ISSN: | 1838-7640 |
Popis: | Rationale: It has been proposed that cancer stem/progenitor cells (or tumor-initiating cells, TICs) account for breast cancer initiation and progression. Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent class-III histone deacetylases and mediate various basic biological processes, including metabolic homeostasis. However, interplay and cross-regulation among the sirtuin family are not fully understood. As one of the least studied sirtuin family members, the mitochondrial sirtuin SIRT4 is a tumor suppressor gene in various cancers. However, its role in cancer stemness, as well as initiation and progression of breast cancer, remains unknown. Methods: The expression of SIRT4 in breast cancer was analyzed using the TCGA breast cancer database and 3 GSEA data. Normal breast epithelial cells MCF10A and breast cancer cell lines MCF-7, MDA-MB-231, BT549, MDA-MB-468 were used to establish SIRT4 gene knockdown and corresponding overexpression cells. Identified MTT cytotoxicity assays, cell invasion and motility assay, sorting of SP, confocal immunofluorescence microscopy, mouse mammary stem cell analysis, glutamine and glucose production, clonogenic and sphere-formation assay, mass spectrometric metabolomics analysis and ChIP-seq to further explore SIRT4 biological role in breast cancer. Results: We elucidated a novel role for SIRT4 in the negative regulation of mammary gland development and stemness, which is related to the mammary tumorigenesis. We also uncovered an inverse correlation between SIRT4 and SIRT1. Most importantly, SIRT4 negatively regulates SIRT1 expression via repressing glutamine metabolism. Besides, we identified H4K16ac and BRCA1 as new prime targets of SIRT4 in breast cancer. Conclusions: These results demonstrate that SIRT4 exerts its tumor-suppressive activity via modulating SIRT1 expression in breast cancer and provide a novel cross-talk between mitochondrial and nuclear sirtuins. |
Databáze: | OpenAIRE |
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