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Sirtuins in Cancer: a Balancing Act between Genome Stability and Metabolism.

Jeong SM, Haigis MC - Mol. Cells (2015)

Bottom Line: Thus, defining the molecules that fine-tune metabolism in response to DNA damage will enhance our understanding of molecular mechanisms of tumorigenesis and have profound implications for the development of strategies for cancer therapy.Sirtuins have been established as critical regulators in cellular homeostasis and physiology.Here, we review the emerging data revealing a pivotal function of sirtuins in genome maintenance and cell metabolism, and highlight current advances about the phenotypic consequences of defects in these critical regulators in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.

ABSTRACT
Genomic instability and altered metabolism are key features of most cancers. Recent studies suggest that metabolic reprogramming is part of a systematic response to cellular DNA damage. Thus, defining the molecules that fine-tune metabolism in response to DNA damage will enhance our understanding of molecular mechanisms of tumorigenesis and have profound implications for the development of strategies for cancer therapy. Sirtuins have been established as critical regulators in cellular homeostasis and physiology. Here, we review the emerging data revealing a pivotal function of sirtuins in genome maintenance and cell metabolism, and highlight current advances about the phenotypic consequences of defects in these critical regulators in tumorigenesis. While many questions should be addressed about the regulation and context-dependent functions of sirtuins, it appears clear that sirtuins may provide a promising, exciting new avenue for cancer therapy.

No MeSH data available.


Related in: MedlinePlus

The regulation of metabolic response to DNA damage by SIRT4. DNA damage-induced SIRT4 represses the metabolism of glutamine (Gln) into TCA cycle, which contributes to the control of cell cycle progression and the maintenance of genomic integrity. Loss of SIRT4 leads to both increased glutaminolysis and DNA damage-induced genomic instability, resulting in tumorigenesis.
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f1-molce-38-9-750: The regulation of metabolic response to DNA damage by SIRT4. DNA damage-induced SIRT4 represses the metabolism of glutamine (Gln) into TCA cycle, which contributes to the control of cell cycle progression and the maintenance of genomic integrity. Loss of SIRT4 leads to both increased glutaminolysis and DNA damage-induced genomic instability, resulting in tumorigenesis.

Mentions: As discussed above, DNA damage elicits signaling pathways that initiate cell cycle arrest and DNA repair. However, the cellular metabolic response to DNA damage is not well elucidated. Recently, we found that SIRT4 functions as a unique “metabolic block” upon genotoxic stress (Jeong et al., 2013). SIRT4 is the most highly induced sirtuins in response to DNA damage stimuli and represses glutamine consumption without affecting glucose uptake, resulting in a decrease in the incorporation of glutamine into the tricarboxylic acid (TCA) cycle intermediates. This metabolic response contributes to cell cycle arrest of damaged cells and promotes the repair of damaged DNA. Indeed, loss of SIRT4 impaired DNA damage-induced cell cycle arrest and resulted in accumulation of DNA damage, and SIRT4 KO MEFs possessed more aneuploidy and exhibited an increased genomic instability (Fig. 1). Additionally, SIRT4 expression is decreased in many human tumors and, importantly, two independently derived SIRT4 KO mice spontaneously develop several types of tumors, most frequently lung tumors (Jeong et al., 2013). These findings identify SIRT4 as a tumor suppressor connecting two hallmarks of cancer: genomic instability and dysregulation of cell metabolism, suggesting that targeting of this link may be clinically beneficial.


Sirtuins in Cancer: a Balancing Act between Genome Stability and Metabolism.

Jeong SM, Haigis MC - Mol. Cells (2015)

The regulation of metabolic response to DNA damage by SIRT4. DNA damage-induced SIRT4 represses the metabolism of glutamine (Gln) into TCA cycle, which contributes to the control of cell cycle progression and the maintenance of genomic integrity. Loss of SIRT4 leads to both increased glutaminolysis and DNA damage-induced genomic instability, resulting in tumorigenesis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588717&req=5

f1-molce-38-9-750: The regulation of metabolic response to DNA damage by SIRT4. DNA damage-induced SIRT4 represses the metabolism of glutamine (Gln) into TCA cycle, which contributes to the control of cell cycle progression and the maintenance of genomic integrity. Loss of SIRT4 leads to both increased glutaminolysis and DNA damage-induced genomic instability, resulting in tumorigenesis.
Mentions: As discussed above, DNA damage elicits signaling pathways that initiate cell cycle arrest and DNA repair. However, the cellular metabolic response to DNA damage is not well elucidated. Recently, we found that SIRT4 functions as a unique “metabolic block” upon genotoxic stress (Jeong et al., 2013). SIRT4 is the most highly induced sirtuins in response to DNA damage stimuli and represses glutamine consumption without affecting glucose uptake, resulting in a decrease in the incorporation of glutamine into the tricarboxylic acid (TCA) cycle intermediates. This metabolic response contributes to cell cycle arrest of damaged cells and promotes the repair of damaged DNA. Indeed, loss of SIRT4 impaired DNA damage-induced cell cycle arrest and resulted in accumulation of DNA damage, and SIRT4 KO MEFs possessed more aneuploidy and exhibited an increased genomic instability (Fig. 1). Additionally, SIRT4 expression is decreased in many human tumors and, importantly, two independently derived SIRT4 KO mice spontaneously develop several types of tumors, most frequently lung tumors (Jeong et al., 2013). These findings identify SIRT4 as a tumor suppressor connecting two hallmarks of cancer: genomic instability and dysregulation of cell metabolism, suggesting that targeting of this link may be clinically beneficial.

Bottom Line: Thus, defining the molecules that fine-tune metabolism in response to DNA damage will enhance our understanding of molecular mechanisms of tumorigenesis and have profound implications for the development of strategies for cancer therapy.Sirtuins have been established as critical regulators in cellular homeostasis and physiology.Here, we review the emerging data revealing a pivotal function of sirtuins in genome maintenance and cell metabolism, and highlight current advances about the phenotypic consequences of defects in these critical regulators in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.

ABSTRACT
Genomic instability and altered metabolism are key features of most cancers. Recent studies suggest that metabolic reprogramming is part of a systematic response to cellular DNA damage. Thus, defining the molecules that fine-tune metabolism in response to DNA damage will enhance our understanding of molecular mechanisms of tumorigenesis and have profound implications for the development of strategies for cancer therapy. Sirtuins have been established as critical regulators in cellular homeostasis and physiology. Here, we review the emerging data revealing a pivotal function of sirtuins in genome maintenance and cell metabolism, and highlight current advances about the phenotypic consequences of defects in these critical regulators in tumorigenesis. While many questions should be addressed about the regulation and context-dependent functions of sirtuins, it appears clear that sirtuins may provide a promising, exciting new avenue for cancer therapy.

No MeSH data available.


Related in: MedlinePlus