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The multifaceted functions of sirtuins in cancer

Key Points

  • Sirtuins are NAD+-dependent enzymes that modulate the activities of target proteins, mediate changes in the metabolic status of cells and regulate diseases of ageing, including neurodegeneration, diabetes, cardiovascular diseases and cancer.

  • Sirtuin 1 (SIRT1) was the first sirtuin to be shown to be involved in cancer. It was demonstrated that SIRT1 represses p53-mediated tumour suppression. Since this finding, SIRT1 has been shown to have both tumour-suppressive and oncogenic roles, depending on the type and stage of cancer.

  • The mitochondrial sirtuin SIRT3 regulates levels of reactive oxygen species (ROS). Loss of SIRT3 results in increased levels of ROS, with subsequent activation of hypoxia-inducible factor 1α (HIF1α) and increased expression of HIF1 target genes, including glycolysis and angiogenesis genes, which favour tumour growth.

  • The mitochondrial sirtuin SIRT4 regulates glutamine metabolism by inhibiting glutamate dehydrogenase (GDH), the rate-limiting enzyme in glutaminolysis. Loss of SIRT4 leads to increased glutamine catabolism, a pathway that promotes tumour growth.

  • The chromatin-bound sirtuin SIRT6 regulates cancer metabolism and inflammation by acting as a co-repressor for HIF1α, MYC and nuclear factor-κB (NF-κB). Loss of SIRT6 results in increased expression of glycolysis, glutaminolysis and ribosomal genes, all of which favour proliferation and tumorigenesis.

  • SIRT1 and SIRT6 promote genomic stability by regulating both single- and double-strand DNA break-repair pathways.

Abstract

The sirtuins (SIRTs; of which there are seven in mammals) are NAD+-dependent enzymes that regulate a large number of cellular pathways and forestall the progression of ageing and age-associated diseases. In recent years, the role of sirtuins in cancer biology has become increasingly apparent, and growing evidence demonstrates that sirtuins regulate many processes that go awry in cancer cells, such as cellular metabolism, the regulation of chromatin structure and the maintenance of genomic stability. In this article, we review recent advances in our understanding of how sirtuins affect cancer metabolism, DNA repair and the tumour microenvironment and how activating or inhibiting sirtuins may be important in preventing or treating cancer.

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Figure 1: Overview of the role of sirtuins in the regulation of cancer metabolism.
Figure 2: Sirtuins regulate multiple steps of the DNA damage response pathways.

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Acknowledgements

The authors thank E. Williams for comments on the manuscript. They apologize to colleagues whose original work could not be cited owing to space limitations. L.G. is supported by the US National Institutes of Health and the Glenn Foundation for Medical Research.

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Correspondence to Leonard Guarente.

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L.G. consults for GlaxoSmithKline, Chronos Therapeutics and Segterra, and he is a founder of Elysium Health. A.C. declares no competing interests.

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Glossary

Glycolysis

The conversion of glucose into pyruvate in a series of enzymatic steps, with the concurrent generation of ATP.

Glutaminolysis

A series of enzymatic reactions in which the amino acid glutamine is converted into glutamate, which can be further metabolized to α-ketoglutarate.

Calorie restriction

A dietary regimen in which all essential nutrients are supplied but calories are reduced by 20–40% compared to ad libitum feeding.

Oxidative metabolism

The oxidation of carbohydrates to CO2 in mitochondria to maximize the production of ATP.

Thymocytes

Haematopoietic progenitor cells that reside in the thymus and differentiate into mature T lymphocytes.

Enterocyte

A type of epithelial cell that resides in the intestine and absorbs nutrients.

Pentose phosphate shunt

An anabolic pathway that converts glucose into pentoses (five-carbon sugars used in nucleotide synthesis), with the concurrent generation of NADPH.

E boxes

DNA sequences found in promoters and recognized by transcription factors that contain the basic helix–loop–helix motif.

Pyrimidine dimers

Covalent linkages of thymine or cytosine bases in DNA that are induced by ultraviolet light.

Interstrand crosslinks

Covalent linkages of complementary strands of DNA that are induced by various exogenous agents (for example, cisplatin) or endogenous agents (for example, aldehydes).

Telomeres

Repetitive nucleotide sequences at the ends of chromosomes that protect them from degradation and fusion with neighbouring chromosomes.

Centromeres

Regions of chromosomes at which two sister chromatids attach to the mitotic spindle for proper segregation during mitosis.

γH2AX

The phosphorylated form of the histone variant H2AX, which marks double-stranded DNA breaks.

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Chalkiadaki, A., Guarente, L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer 15, 608–624 (2015). https://doi.org/10.1038/nrc3985

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