Pharmacological and genetic perturbation establish SIRT5 as a promising target in breast cancer
| Autor: | Dennis A Kutateladze, Hening Lin, Bo Li, Johan Auwerx, Yashira L Negrón Abril, Bin He, Jessica Jingyi Bai, Jun Young Hong, Ying-Ling Chiang, Ravi Dhawan, Fangyu Wang, Qingjie Zhao, Brenna Remick, Robert S. Weiss, Viviana Maymi, Richard A. Cerione, Irma Fernandez, Sushabhan Sadhukhan, Teresa L. Southard, James Mullmann, Min Yang, Jing Hu |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research antioxidant medicine.disease_cause Mice Succinylation 0302 clinical medicine Sirtuins Enzyme Inhibitors Mice Knockout Mammary tumor Isocitrate Dehydrogenase 030220 oncology & carcinogenesis Knockout mouse Sirtuin Heterografts Female regulators SIRT5 malonylation Breast Neoplasms Deacylase Biology Article 03 medical and health sciences Breast cancer Cell Line Tumor expression Breast Cancer Genetics medicine Animals Humans Molecular Biology Cancer medicine.disease Oxidative Stress 030104 developmental biology Cancer research biology.protein desuccinylation progression demalonylase protein Reactive Oxygen Species Carcinogenesis metabolism |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-020-01637-w |
| Popis: | SIRT5 is a member of the sirtuin family of NAD(+)-dependent protein lysine deacylases implicated in a variety of physiological processes. SIRT5 removes negatively charged malonyl, succinyl, and glutaryl groups from lysine residues and thereby regulates multiple enzymes involved in cellular metabolism and other biological processes. SIRT5 is overexpressed in human breast cancers and other malignancies, but little is known about the therapeutic potential of SIRT5 inhibition for treating cancer. Here we report that genetic SIRT5 disruption in breast cancer cell lines and mouse models caused increased succinylation of IDH2 and other metabolic enzymes, increased oxidative stress, and impaired transformation and tumorigenesis. We, therefore, developed potent, selective, and cell-permeable small-molecule SIRT5 inhibitors. SIRT5 inhibition suppressed the transformed properties of cultured breast cancer cells and significantly reduced mammary tumor growth in vivo, in both genetically engineered and xenotransplant mouse models. Considering that Sirt5 knockout mice are generally normal, with only mild phenotypes observed, these data establish SIRT5 as a promising target for treating breast cancer. The new SIRT5 inhibitors provide useful probes for future investigations of SIRT5 and an avenue for targeting SIRT5 as a therapeutic strategy. |
| Databáze: | OpenAIRE |
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