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Review
. 2019 Jan;17(1):729-738.
doi: 10.3892/ol.2018.9722. Epub 2018 Nov 16.

Sirtuin 1 and oral cancer

Shajedul Islam  1 , Yoshihiro Abiko  2 , Osamu Uehara  1   3 , Itsuo Chiba  1
Affiliations
Review

Sirtuin 1 and oral cancer

Shajedul Islam et al. Oncol Lett. 2019 Jan.

Abstract

The sirtuins (SIRTs) are a family of highly conserved histone deacetylases (HDACs) consisting of seven members (SIRT1-SIRT7). Over the past few decades, SIRT1 has been the most extensively studied and garnered tremendous attention in the scientific community due to its emerging role in cancer biology. However, its biological role in the regulation of oral cancer is not yet fully understood. Owing to contradictory findings regarding the role of SIRT1 in oral cancer, debate about it continues. The present study discusses the biological roles and potential therapeutic implications of SIRT1 in precancerous oral lesions and oral cancer.

Keywords: betel quid; oral cancer; sirtuin; transforming growth factor beta.

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Figures

Figure 1.
Figure 1.
The subcellular localizations of sirtuins, their enzymatic activities, substrates, and functions: H3K9ac, H3K26ac, H3K16ac, HIF-1α/2α, Foxo3a, SOD2, SMAD2/3, H3K56ac, H4K16ac, EIF5a, G6PD, H4K14ac, IDH2, GOT2, ADP; GDH, PDH, CPS1, PARP1, NF-Kb and PPAR-γ. SIRT1 is predominantly located in the nucleus, and also in the cytosol. SIRT2 is localized in the cytosol. SIRT3, SIRT4, and SIRT5 are mitochondrial proteins. SIRT6 and SIRT7 are localized in the nucleus. H3K9ac, histone H3 lysine 9 acetylation; H3K26ac, histone H3 lysine 26 acetylation; H3K16ac, histone H3 lysine 16 acetylation; HIF-1α/2α, hypoxia-inducible factor-1/2 alpha; Foxo3a, forkhead box o3 alpha; SOD2, superoxide dismutase 2; SMAD2/3, mothers against decapentaplegic homolog 2/3; H3K56ac, histone H3 lysine 56 acetylation; H4K16ac, histone H4 lysine 16 acetylation; EIF5a, eukaryotic translation initiation factor 5a; G6PD, glucose-6-phosphate dehydrogenase; H4K14ac, histone H4 lysine 14 acetylation; IDH2, isocitrate dehydrogenase 2; GOT2, glutamic-oxaloacetic transaminase; ADP, adenosine diphosphate; GDH, glutamate dehydrogenase; PDH, pyruvate dehydrogenase; CPS1, carbamoyl phosphate synthetase 1; PARP1, poly (ADP-ribose) polymerase 1; NF-Kb, nuclear factor kappa-light-chain-enhancer of activated B cells; PPAR-γ, peroxisome proliferator-activated receptors gamma.
Figure 2.
Figure 2.
Possible regulatory mechanism of SIRT1 in oral cancer induced by betel quid chewing: (A, a) TGF-β is a growth factor and its overexpression has been frequently reported in precancerous oral lesions leading to oral cancer, The TGF-β ligand binds to its receptor and induces the phosphorylation of smad2/3; (A, b) phosphorylated smad2/3 binds with acetylated smad4 and forms a complex known as the SMAD complex; (A, c, d) this SMAD complex translocates to the nucleus and binds with its co-activator CBP/p300, a histone acetyltransferase, and induces TGF-β-mediated invasion and metastasis. (A, e) SIRT1 can inhibit phosphorylation of smad2/3 and remove acetyl groups from smad4 protein. These effects help to prevent the formation of the SMAD complex; (A, f) at the nucleus, SIRT1 binds in the promoter region of TGF-β, inhibits CBP/p300-mediated acetylation via the deacetylation mechanism and results in transcriptional suppression of TGF-β-mediated malignant transformation, invasion, and metastasis in the oral mucosa of betel quid chewers. (B, a) Arecoline is the major alkaloid in betel quid, and is known to downregulate SIRT1 expression in oral epithelial cells, leading to enhanced TGF-β-mediated invasion and metastasis; (B, b) arecoline-mediated downregulation of SIRT1, followed by upregulation of TGF-β, acts on fibroblasts and enhances the pathogenesis of OSF, a precancerous condition. SIRT1, sirtuin 1; TGF-β, transforming growth factor beta; OSF, oral submucous fibrosis.
Figure 3.
Figure 3.
Latent TGF-β structure and activation of TGF-β: (A) after synthesizing TGF-β inside the cytoplasm of a cell, LAP forms a straightjacket around the TGF-β, resulting in a small latent complex; (B) this small latent complex binds to LTBP to form a LLC; (C) this is an inactive state of TGF-β, which is now secreted in the ECM; (D) in the ECM, cell-associated αvβ6 integrin binds to the arginyl-glycyl-aspartic acid (RGD) domain of the latency-associated peptide, cleaving the LTBP interaction; (E) TGF-β is then released from the LAP, allowing it to interact with its receptor and activate TGF-β-mediated downstream targets. LAP, latency-associated peptide; LTBP, latent TGF-β-binding protein; LLC, large latent complex; ECM, extracellular matrix.
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