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

• Published in: Cell reports (Cambridge) 2018-02, Vol.22 (8), p.1945-1955
• Main Authors: Gonzalez Herrera, Karina N., Zaganjor, Elma, Ishikawa, Yoshinori, Spinelli, Jessica B., Yoon, Haejin, Lin, Jia-Ren, Satterstrom, F. Kyle, Ringel, Alison, Mulei, Stacy, Souza, Amanda, Gorham, Joshua M., Benson, Craig C., Seidman, Jonathan G., Sorger, Peter K., Clish, Clary B., Haigis, Marcia C.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; azaserine; Azaserine - pharmacology; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; glutamine; Glutamine - metabolism; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice, Knockout; Mice, Nude; mitochondria; mTORC1; nucleotide synthesis; Nucleotides - biosynthesis; proliferation; Promoter Regions, Genetic - genetics; Signal Transduction - drug effects; SIRT3; sirtuin; Sirtuin 3 - deficiency; Sirtuin 3 - metabolism; Small Molecule Libraries - pharmacology; small-molecule screen; Up-Regulation - drug effects
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.01.076

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. [Display omitted] •A small-molecule screen identifies inhibitors of SIRT3 knockout cell proliferation•SIRT3 knockout cells are dependent on glutamine for proliferation•Loss of SIRT3 results in mTORC1-mediated glutamine incorporation into nucleotides•SIRT3 suppresses mTORC1 signaling and growth in an in vivo breast cancer model SIRT3 is lost or downregulated in numerous pathologies. Loss of SIRT3 results in increased cell proliferation. Gonzalez Herrera et al. identify glutamine incorporation into nucleotides to be a driving force behind increased proliferation of cells lacking SIRT3.