Role of sirtuins in esophageal cancer: Current status and future prospects

Table 1 Roles of sirtuins in cancer control

	Role	Effect	Involved pathway or mechanism
SIRT1	Promotor	Promote proliferation	p53, FOXO family member, E2F1, p73, RB, Ku70, SFRP1, SFRP2, GATA4, GATA5, MLH1
		Inhibit apoptosis	p53, NF-κβ, FOXO3, Ku70, AKT, MAPK, NRF2
		Induce EMT, promote migration and metastasis	ZEB1
	Suppressor	Inhibit tumor formation and proliferation	β-catenin
		Induce apoptosis	survivin
		Inhibit EMT	SMAD4, TGF-β signaling on MMP7
SIRT2	Promotor	Promote proliferation	Mediating immune evasion, altering the alkaline environment
		Inhibit apoptosis	cMYC
		Promote invasion and migration	Stimulating mitochondrial metabolism, mediating EMT
	Suppressor	Inhibit proliferation	Inhibiting fibroblast activity and tumor angiogenesis
		Inhibit invasion and migration	MMP9, E-cadherin
SIRT3	Promotor	Inhibit apoptosis and promote proliferation	p53, SHMT2, IDH2
		Promote invasion and metastasis	Reprogramming fatty acid metabolism
	Suppressor	Induce cell arrest and apoptosis	Bcl-2, p53, HIF1α, PDC, SOD2, GOT2
		Inhibit EMT and migration	FOXO3A, Wnt / β-catenin pathway
		Inhibit tumorigenesis	PDH
SIRT4	Promotor	Promote proliferation	PTEN
	Suppressor	Inhibit glutamine metabolism and proliferation	mTORC1 pathway
		Inhibit EMT, invasion and migration	E-cadherin
		Induce G1 cell cycle arrest	Cyclin D, cyclin E
SIRT5	Promotor	Promote proliferation	GLUD1, SHMT2, NRF2, PKM2, SUN2
		Inhibit mitochondrial apoptosis	Cyt c
		Promote autophagy	AMPK–mTOR pathway
		Promote invasion and migration	E2F1
		Promote resistance to chemotherapy	SDHA
	Suppressor	Inhibit carcinoma development	ACOX1
		Inhibit proliferation	SOD1
		Represent protective mechanism for tumor cells	Inhibiting ammonia-induced autophagy
SIRT6	Promotor	Promote proliferation and inhibit apoptosis	ERK1/2 pathway, AKT
		Promote invasion and migration	ERK1/2/MMP9 signaling
		Contribute to cancer development and progression	Regulating autophagy
	Suppressor	Inhibit proliferation	PCBP2, ERK1/2
		Inhibit Warburg effect	HIF-1α
		Induce apoptosis	NF-κβ, Bax, survivin
		Inhibit proliferation, invasion and migration	PKM2
SIRT7	Promotor	Promote proliferation	ERK1/2, H3K18ac
		Inhibit apoptosis	miR34a, NF-κβ family subunits, mTOR/IGF2 pathway
		Promote invasion	Vimentin, fibronectin, E-cadherin, β-catenin
	Suppressor	Inhibit proliferation and invasion	SMAD4
		Inhibit EMT	TGF-β signaling

ACOX1: Acyl-CoA oxidase 1; AKT: Protein kinase B; Bax: BCL2 associated X; β-catenin: Catenin beta; Cyt c: Cytochrome C; E2F1: E2F transcription factor 1; E-cadherin: Cadherin 1; ERK1/2: Extracellular signal-regulated kinases 1/2; FOXO: Forkhead class O transcription factor; GLUD1: Glutamate dehydrogenase 1; GOT2: Glutamic-oxaloacetic transaminase 2; H3K18ac: Histone H3 lysine 18 acetylation; HIF1α: Hypoxia inducible factor 1 subunit alpha; IDH2: Isocitrate dehydrogenase 2; IGF2: Insulin like growth factor 2; MAPK: Mitogen-activated protein kinase; MLH1: MutL homolog 1; MMP7: Matrix metallopeptidase 7; MMP9: Matrix metallopeptidase 9; mTOR: Mammalian target of rapamycin; mTORC1: Mammalian target of rapamycin complex 1; NF-κB: Nuclear factor kappa B; NRF2: Nuclear factor erythroid 2-related factor 2; p53: Protein 53; p73: Protein 73; PCBP2: Poly(rC) binding protein 2; PDH: Pyruvate dehydrogenase; PKM2: Pyruvate kinase M2; PTEN: Phosphatase and tensin homolog; RB: Retinoblastoma protein; SDHA: Succinate dehydrogenase complex flavoprotein subunit A; SFRP: Secreted Frizzled-related protein; SHMT2: Serine hydroxymethyl transferase 2; SIRT: Sirtuin; SMAD4: SMAD family member 4; SOD1: Superoxide dismutase 1; SOD2: Superoxide dismutase 2; SUN2: Sad1 and UNC84 domain containing 2; TGF-β: Transforming growth factor beta; ZEB1: Zinc finger E-box binding homeobox 1.

Table 2 Roles of sirtuins in esophageal cancer

	Type	Role	Effect	Ref.
SIRT1	ESCC	Promotor	Suppression of SIRT1 inhibits cell proliferation, cell migration, and EMT in ESCC cell line	[22,23]
			SIRT1 expression is associated with poor prognosis	[23-27,34]
			SIRT1 enhances chemotherapy and chemoradiotherapy resistance	[29-32]
			Rapamycin suppresses cell viability, migration, invasion by negatively regulating SIRT1	[35]
	EAC		SIRT1 is associated with poor overall survival	[28]
			SIRT1 is a useful biomarker for high-grade dysplasia and cancer of Barrett's esophagus	[33]
			Sirtinol, SIRT1 inhibitor, inhibits cell viability, affects proliferation in the long term, and potentially suppresses resistant and recurrent tumors under hypoxic conditions	[36]
SIRT2	ESCC	Promotor	SIRT2 expression was associated with tumor invasion, lymph node metastasis, advanced clinical stage, poor progression-free survival, and overall survival	[47]
	EAC	Suppressor	Dysregulation of SIRT2 is associated with poor prognosis	[48,49]
SIRT3	ESCC	Promotor	Serum SIRT3 levels are higher in ESCC patients compared to those in the control subjects	[63]
			SIRT3 induces the proliferation inhibition and apoptosis	[64]
			High SIRT3 expression is associated with poor survival outcome	[65,66]
	EAC		No report
SIRT4	ESCC	Suppressor	SIRT4 rescues the promoting effect of miR-424-5p on ESCC cell proliferation and migration	[76]
			Low SIRT4 expression is associated with a high distant recurrence rate and poor prognosis, and in vitro, knockdown of SIRT4 promotes cell proliferation and migration	[77]
	EAC		No report
SIRT5	ESCC		No report
	EAC
SIRT6	ESCC	Promotor	SIRT 6 is overexpressed in ESCC tissues and that it also promotes cell proliferation and induces the expression of Bcl2, an important anti-apoptotic factor, and autophagy in ESCC cells	[102]
	EAC		No report
SIRT7	ESCC		No report
	EAC

EAC: Esophageal adenocarcinoma; EMT: Epithelial-mesenchymal transition; ESCC: Esophageal squamous cell carcinoma; SIRT: Sirtuin.