锡尔图因
生物
癌变
琥珀酰化
癌症
癌症研究
赖氨酸
癌细胞
生物化学
酶
NAD+激酶
遗传学
氨基酸
作者
Yashira L. Negrón Abril,Irma Fernández,Jun Young Hong,Ying‐Ling Chiang,Dennis A. Kutateladze,Qingjie Zhao,Min Yang,Jing Hu,Sushabhan Sadhukhan,Bo Li,Bin He,Brenna C. Remick,Jessica Jingyi Bai,James Mullmann,Fangyu Wang,Viviana I. Maymí,Ravi Dhawan,Johan Auwerx,Teresa Southard,Richard A. Cerione,Hening Lin,Robert S. Weiss
出处
期刊:Oncogene
[Springer Nature]
日期:2021-01-21
卷期号:40 (9): 1644-1658
被引量:50
标识
DOI:10.1038/s41388-020-01637-w
摘要
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.
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