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
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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