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. 2017 Dec;16(6):1208-1218.
doi: 10.1111/acel.12685. Epub 2017 Oct 10.

Sirtuins at the Crossroads of Stemness, Aging, and Cancer

Free PMC article

Sirtuins at the Crossroads of Stemness, Aging, and Cancer

Carol O'Callaghan et al. Aging Cell. .
Free PMC article


Sirtuins are stress-responsive proteins that direct various post-translational modifications (PTMs) and as a result, are considered to be master regulators of several cellular processes. They are known to both extend lifespan and regulate spontaneous tumor development. As both aging and cancer are associated with altered stem cell function, the possibility that the involvement of sirtuins in these events is mediated by their roles in stem cells is worthy of investigation. Research to date suggests that the individual sirtuin family members can differentially regulate embryonic, hematopoietic as well as other adult stem cells in a tissue- and cell type-specific context. Sirtuin-driven regulation of both cell differentiation and signaling pathways previously involved in stem cell maintenance has been described where downstream effectors involved determine the biological outcome. Similarly, diverse roles have been reported in cancer stem cells (CSCs), depending on the tissue of origin. This review highlights the current knowledge which places sirtuins at the intersection of stem cells, aging, and cancer. By outlining the plethora of stem cell-related roles for individual sirtuins in various contexts, our purpose was to provide an indication of their significance in relation to cancer and aging, as well as to generate a clearer picture of their therapeutic potential. Finally, we propose future directions which will contribute to the better understanding of sirtuins, thereby further unraveling the full repertoire of sirtuin functions in both normal stem cells and CSCs.

Keywords: EMT; Sirtuins; aging; calorie restriction; cancer; stem cells.


Figure 1
Figure 1
Schematic representation of sirtuin roles in Hedgehog, Wnt/β‐catenin, and Notch stem cell signaling pathways. By interacting with BCL6 and BCOR, Sirt1 represses Sonic Hedgehog effectors Gli1 and Gli2. Sirt1 promotes Wnt/β‐catenin signaling by deacetylating β‐catenin and FOXO transcription factors and by suppressing Wnt pathway antagonists SFRP2 and DACT1. Sirt2, however, inhibits β‐catenin signaling and downregulates expression of Wnt target genes, while Sirt6 represses Wnt target genes by interacting with LEF1 and deacetylating histone 3. With the focus on Notch pathway, Sirt1 deacetylates and destabilizes the NICD. Sirt1 also cooperates with LSD1 to repress Notch target genes. ADAMs, a disintegrin and metalloproteases; APC, adenomatous polyposis coli; CK1α, casein kinase 1α; CSL/RBPJ, CBF1 Suppressor of Hairless LAG‐1/recombination signal binding protein for immunoglobulin κ J region; Dvl, Disheveled; GSK3β, glycogen synthase kinase‐3β; LEF/TCF, lymphoid enhancer factor/T‐cell factor; LSD1, lysine demethylase 1A; LRP5/6, low‐density lipoprotein‐related proteins 5 and 6; NICD, Notch intracellular domain; SHH, Sonic Hedgehog; β‐cat, β‐catenin; γ‐sec, γ‐secretase.
Figure 2
Figure 2
Schematic representation of positive and negative regulation of EMT by sirtuins. Positive: TGF‐β signaling is associated with an increase in Sirt1. Sirt1 is recruited by Zeb1 to the E‐cadherin promoter and causes transcriptional repression. Similarly, Sirt1 interacts with Twist and MBD1 to silence the E‐cadherin promoter. Sirt1 may also recruit Sirt7 to repress E‐cadherin expression. Sirt2 activates Akt/GSK3β/β‐catenin signaling to promote EMT. Deacetylation of Slug by Sirt2 promotes Slug protein stability and repression of Slug target genes, including E‐cadherin. Negative: Sirt1 inhibits TGF‐β signaling by deacetylating Smad4. This decreases MMP transcription and E‐cadherin degradation. Sirt4 upregulates E‐cadherin expression via its repression of glutamine metabolism. E‐cad, E‐cadherin; GSK3β, glycogen synthase kinase‐3β; MBD1, methyl‐CpG binding domain protein‐1; MMP7, metalloproteinase 7; TGF‐βR, transforming growth factor‐β receptor; β‐cat, β‐catenin.

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