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

• DOI: 10.1016/j.celrep.2018.01.076
• Publication Date: 2018-02-23T15:43:50Z
• Authors: Karina N. Gonzale...; Elma Zaganjor; Yoshinori Ishikawa; Jessica B. Spinelli; Haejin Yoon; Jia-Ren Lin; F. Kyle Satterstrom; Alison Ringel; Stacy Mulei; Amanda Souza; Joshua M. Gorham; Craig C. Benson; Jonathan G. Seidman; Peter K. Sorger; Clary B. Clish; Marcia C. Haigis
• Keywords: 0301 basic medicine; 570; QH301-705.5; Glutamine; 610; Mice, Nude; Breast Neoplasms; nucleotide synthesis; Mechanistic Target of Rapamycin Complex 1; Article; SIRT3; Small Molecule Libraries; 03 medical and health sciences; Cell Line, Tumor; Sirtuin 3; 616; Animals; Amino Acid Sequence; Biology (General); Promoter Regions, Genetic; mTORC1; Azaserine; Cell Proliferation; Mice, Knockout; Nucleotides; Fibroblasts; Up-Regulation; 3. Good health; mitochondria; sirtuin; glutamine; Female; Signal Transduction

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.