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

Publication date: 20 February 2018
Source:Cell Reports, Volume 22, Issue 8
Author(s): Karina N. Gonzalez Herrera, 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
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.

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Teaser

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.


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