Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3

Cell Reports
Karina N Gonzalez HerreraMarcia C Haigis

Abstract

Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells. Furthermore, we found that SIRT3 KO cells upregulated the diversion of glutamine into de novo nucleotide synthesis through hyperactive mTORC1 signaling. Overexpression of SIRT3 suppressed mTORC1 and growth in vivo in a xenograft tumor model of breast cancer. Thus, we have uncovered a metabolic vulnerability of cells with SIRT3 loss by using an unbiased small-molecule screen.

Citations

Jun 30, 2019·Cell Cycle·Luis Filipe Costa-Machado, Pablo J Fernandez-Marcos
Sep 22, 2019·International Journal of Molecular Sciences·David L Newman, Stephen L Gregory
Sep 12, 2020·Cell Communication and Signaling : CCS·Emma BarrosoManuel Vázquez-Carrera
May 23, 2019·Cell Reports·Timothy C KennyDoris Germain
Jun 15, 2021·Frontiers in Oncology·Wanyan WangJin Huang
Dec 19, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Tingting JiangWen Xue
Aug 4, 2021·Trends in Endocrinology and Metabolism : TEM·Yi LiuShuang Tang
Aug 8, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Chunfang WangLi Shen

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Datasets Mentioned

BETA
GSE109279

Methods Mentioned

BETA
xenograft

Software Mentioned

MetaboAnalyst
DESeq2
MotifADE

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