The role of SIRT6 in tumors

Abstract

Dysfunctional DNA-damage response and consequent genomic instability play a pivotal role in the initiation and progression of both solid and hematologic tumors. Preservation of DNA integrity is, in fact, a key cellular function, hence several mechanisms that repair the damaged DNA need to be studied. Recent studies have focused on key players that are able to improve the DNA repair and thus may act as targets for new therapeutic approaches.Several data have been obtained on overexpression and hyperactivity of Sirtuins (SIRTs), a family of proteins with deacylase or mono-adenosine diphosphate (ADP)-ribosyltransferase activities that degrade nicotinamide adenine dinucleotide (NAD + ) enzymes to enable their biological processes 1 and promote longevity. 2 In mammalian cells, the Sirtuin family is composed of seven members that show different subcellular localization and functions (transcription, metabolism, fat mobilization, DNA repair, stress responses, apoptosis, tumorigenesis and aging), 3,4 and conserve the catalytic domain and the NAD + binding site. 5 In cancer and agingassociated pathways, SIRT6 is crucial since it prevents genomic instability, maintains telomere integrity, and regulates metabolic homeostasis and DNA repair. 6 SIRT6 can be considered a double-edged sword in cancer because of its dual role of both tumor suppressor and oncogene (Table 1). In healthy conditions, SIRT6 either acts as a gatekeeper of DNA repair mechanisms or regulates cell survival and proliferation. Following the DNA damage, SIRT6 triggers the apoptotic process, hence it is down-regulated in several cancers. However, in other cancers, it is up-regulated, corroborating the idea that it can also act as oncogene. SIRT6 as a tumor suppressorStudies in colorectal, breast, ovarian, hepatocellular, lung, and other tumors correlate the reduction of SIRT6 expression with tumor progression and poor clinical outcome. In the presence of DNA-damage, SIRT6 promotes apoptotic cell death, ensuring damaged cells do not proliferate. Sebastian et al. 7 demonstrated in vivo that SIRT6 deficiency favors tumor growth and invasiveness. They also showed that SIRT6 is involved in the Warburg effect, a glycolytic metabolic shift important for supporting rapid tumor growth. SIRT6 promotes both in vitro and in vivo tumor suppression through repression of hypoxia-inducible factor 1-alpha (HIF-1α) that inhibits glycolytic metabolism in cancer cells.7 Interestingly, in mouse and human pancreatic ductal adenocarcinoma (PDAC), the SIRT6 knockdown is due to repression of Myc-target oncofetal protein Lin28b that negatively regulates the let-7 family of miRNAs. 8 In detail, loss of SIRT6 triggers activation of Lin28 promoter, Myc recruitment, and consequent activation of Lin28b, the downstream let-7 target genes (HMGA2, IGF2BP1) and IGF2BP3 that accelerate the PDAC progression and metastasis. 8 In human colon cancer, Lin et al. 9 discovered the crosstalk between UPS10 and SIRT6 that regulates cell-cycle progression and proliferation, and showed that the dysregul...

The clinical and prognostic significance of FOXN3 downregulation in acute myeloid leukaemia

“…Acting as a tumour suppressor gene, FOXN3 is reduced in several types of tumours, such as HCC, colon cancer and osteosarcoma, but it is upregulated in ovarian cancer and breast cancer, where it acts as an oncogene . One explanation for the diverse effects of FOXN3 may be due to the specific cellular and tissue environment . In our previous studies, the forced expression of FOXN3 inhibited cell proliferation, the induction of apoptosis, and cell cycle arrest .…”

“…11,29 One explanation for the diverse effects of FOXN3 may be due to the specific cellular and tissue environment. 30,31 In our previous studies, the forced expression of FOXN3 inhibited cell proliferation, the induction of apoptosis, and cell cycle arrest. 21 These results indicated that FOXN3 may participate in the malignant transformation of leukaemia cells.…”

Dual Tumor Suppressor and Tumor Promoter Action of Sirtuins in Determining Malignant Phenotype

“…In these tumors, expression levels of SIRT6 are decreased and aerobic glycolysis pathways are blocked. In other cancer types, such as lung cancer (Desantis et al, 2018), prostate cancer (Bai et al, 2016), melanoma, and non-melanoma skin cancer (Garcia-Peterson et al, 2017), SIRT6 is upregulated both at mRNA and protein level, and acts as an oncogene responsible for cancer cell proliferation.…”

Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies

“…Inhibition of cytoplasmic SIRT1 promotes caspase-2-dependent apoptosis in breast cancer cells by promoting dissociation of its negative regulator, 14-3-3ζ (Andersen et al, 2011). SIRT6 functions as a master regulator of metabolic programming and maintains genome integrity during tumorigenesis (Desantis, Lamanuzzi, & Vacca, 2018). SIRT6 has high tumorigenic activity, and high expression of SIRT6 in colon cancer samples has been shown to correlate with poor prognosis (Geng et al, 2018).…”