Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3
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
Affiliations
Karina N. Gonzalez Herrera
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA
Elma Zaganjor
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA
Yoshinori Ishikawa
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Jessica B. Spinelli
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA
Haejin Yoon
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA
Jia-Ren Lin
Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA
F. Kyle Satterstrom
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Alison Ringel
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA
Stacy Mulei
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Amanda Souza
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Joshua M. Gorham
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Craig C. Benson
Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
Jonathan G. Seidman
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Peter K. Sorger
Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Clary B. Clish
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Marcia C. Haigis
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA; Corresponding author
Summary: 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.
