lNTRODUCTlON

Esophageal cancer (EC) is the seventh leading cause of morbidity and the sixth leading cause of mortality worldwide[1], and the prognosis of advanced EC patients is extremely poor[2]. Therefore, identifying specific molecular markers that can be used as prognostic markers or therapeutic targets for EC is highly desirable to aid in the personalization and improvement of the precision of medical treatment, which can prevent side effects and extra expenses, thereby leading to a more effective multidisciplinary treatment.

Sirtuins are a highly conserved family of proteins that exist in a wide range of prokaryotic and eukaryotic organisms, and their functional activity is dependent on the cofactor nicotinamide adenine dinucleotide (NAD+)[3]. The mammalian sirtuin family is a homolog of the yeast silent information regulator 2 (Sir2) protein and consists of seven members: SIRT1-7. Sirtuins are distinguished by their subcellular localization: SIRT1, SIRT6 and SIRT7 are mainly found in the nucleus; SIRT3, SIRT4 and SIRT5 are mainly located in the mitochondria; and SIRT2 is mainly found in the cytoplasm. Furthermore, the SIRT family proteins have conserved domains in their core catalytic activities, with SIRT1, SIRT2 and SIRT3 designated as class I; SIRT4 designated as class II; SIRT5 designated as class III; and SIRT6 and SIRT7 designated as class IV (Figure 1)[4]. Sirtuins are involved in the regulation of various biological functions, such as apoptosis, metabolism, stress response, aging, differentiation and cell cycle progression[5]. However, while the role of sirtuins in cancer progression has been investigated over the past few years, their precise role remains difficult to characterize, as they have both cancerpromoting and cancer-suppressing properties, depending on the type of cancer[6]. These conflicting characteristics make research into the nature of sirtuins all the more fascinating.

So nothing was left for them but to take their departure to the cottage, which stood in the midst of a dark forest, and seemed to be the most dismal8 place upon the face of the earth

In EC, the clinical impact of sirtuins remains unclear due to the limited number of reports concerning sirtuins in EC. Therefore, this is the first review to focus on sirtuins in the field of EC. In this review, we will briefly summarize the role of sirtuins in cancer and discuss the current findings and future prospects of sirtuins in EC.

LlTERATURE SEARCH

PubMed was searched to identify studies on sirtuins and cancer from inception until January 2022. The following search terms were applied: “Sirtuin” or “Silent mating type information regulation 2 homolog” or “SIRT” and “carcinoma” or “cancer”. The reference lists of all related articles were screened for other potentially relevant studies.

SlRT1

In EC, SIRT4 has been reported as a tumor suppressor (Table 2). Cui

[76] revealed that SRT4 was negatively regulated by miR-424-5p, and overexpression of SIRT4 strongly rescued the promoting effect of miR-424-5p on ESCC cell proliferation and migration capacity. In addition, Nakahara

[77] reported that a low SIRT4 expression was significantly associated with a high distant recurrence rate and poor prognosis, and

, knockdown of SIRT4 promoted glutamine dehydrogenase activity and stimulated cell proliferation and migration.

，。，、。，()。，、， ，。： ! 。Each day the children produced some new wonder -- strings3 of popcorn4, hand-made trinkets, and German bells made from wallpaper samples, which we hung from the ceiling

I started to talk to some friends nearby when there was a tug9 on my sleeve, my arm was pulled over by a determined10 young Josh Frager, and he began putting a multicolored, woven yarn11 bracelet12 around my wrist

The relationship between the SIRT5 expression and clinical prognosis has also been reported to vary by cancer type[78,90].

However, SIRT1 has also been reported to function as a tumor suppressor through the following mechanisms: (1) SIRT1 inhibits tumor formation and proliferation by deacetylating catenin beta (βcatenin) in colon cancer[19]; (2) SIRT1 induces apoptosis in breast cancer 1 (BRCA1)-related breast cancer by suppressing survivin, an inhibitor of apoptosis[20]; and (3) SIRT1 suppresses EMT in cancer by deacetylating SMAD family member 4 (SMAD4) and inhibiting the effect of transforming growth factor beta (TGF-β) signaling on matrix metallopeptidase 7 (MMP7), a target gene of SMAD4[21].

In EC, SIRT1 has been reported as a tumor-promoting factor (Table 2). Suppression of SIRT1 inhibits cell proliferation, cell migration and EMT in esophageal squamous cell carcinoma (ESCC) cell line[22,23]. SIRT1 has been suggested to be useful as a biomarker in EC as follows: (1) It has been reported that SIRT1 expression is associated with a poor prognosis in both ESCC and esophageal adenocarcinoma (EAC)[23-28]; (2) SIRT1 has also been demonstrated to be related to chemotherapy and chemoradiotherapy resistance in several ESCC studies[29-32]; and (3) SIRT1 has been described to be a useful biomarker for high-grade dysplasia and cancer of Barrett's esophagus[33]. Furthermore, we conducted a meta-analysis of these articles and demonstrated that a high expression of SIRT1 was correlated with a poor overall survival (OS), deeper tumors and a more advanced TNM stage in patients with ESCC[34]. In addition, recent studies have reported the potential utility of SIRT1 as a therapeutic target in EC. Liu

[35] reported that rapamycin suppressed cell viability, migration, invasion and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways in EC by negatively regulating SIRT1. Jiang

[36] reported that sirtinol inhibited cell viability in EAC in a dose-dependent manner, affected proliferation in the long term and potentially suppressed resistant and recurrent tumors under hypoxic conditions. Taken together, these reports suggest that SIRT1 inhibition may play an important role in the therapeutic field of EC.

SlRT2

Similar to SIRT1, SIRT2 has been reported to have both tumor-promoting and tumor-suppressing effects depending on the cancer type (Table 1 and Figure 2).

In contrast, a small number of studies have reported the function of SIRT4 as a tumor-promoting factor (Table 1). Jeong

[74] demonstrated that the overexpression of SIRT4 protected cancer cells from DNA damage or endoplasmic reticulum stress, and conversely, the loss of SIRT4 sensitized cells after drug treatment. Furthermore, when cells are starved of nutrients, SIRT4 cooperates with insulindegrading enzymes to degrade phosphatase and tensin homolog (PTEN), a tumor-suppressing factor, and promote the survival of cancer cells[75].

Conversely, SIRT2 has been reported as a tumor suppressor that inhibits the growth of tumor cells through interaction with the tumor microenvironment, such as by inhibiting fibroblast activity and tumor angiogenesis[39]. In addition, the increased expression of matrix metalloproteinase 9 (MMP9) and decreased expression of cadherin 1 (E-cadherin) were shown to promote cell migration and invasion in SIRT2-deficient mouse embryonic fibroblasts[43]. In addition, a low expression of SIRT2 is reportedly associated with a poor prognosis in prostate cancer[44], cervical cancer[45] and colorectal cancer[46].

And thus they tore on and on, and a long time went by, and then yet more time passed, and still they were above the sea, and the North Wind grew tired, and more tired, and at last so utterly22 weary that he was scarcely able to blow any longer, and he sank and sank, lower and lower, until at last he went so low that the waves dashed against the heels of the poor girl he was carrying

In EC, Yan

[47] reported that SIRT2 expression was associated with tumor invasion, lymph node metastasis, advanced clinical stage, a poor progression-free survival and the OS in ESCC patients (Table 2). In contrast, SIRT2 has been reported to be a tumor suppressor in EAC. Ong

[48] revealed that dysregulation of SIRT2 significantly increased the hazard ratio of death. Peters

[49] also demonstrated that the dysregulation of SIRT2 was significantly associated with a poor prognosis in esophageal and junctional adenocarcinoma.

SlRT3

Whether SIRT3, a major mitochondrial deacetylase, functions as a tumor promoter or suppressor remains controversial (Table 1 and Figure 2).

SIRT3 regulates deacetylation to a variety of substrates, including p53, serine hydroxymethyltransferase 2 (SHMT2) and isocitrate dehydrogenase 2 (IDH2), preventing apoptosis and promoting cell proliferation[50-52]. In addition, Li

[53] showed that SIRT3 promotes infiltration and metastasis of cervical cancer cells by reprogramming fatty acid metabolism.

In contrast, many studies have suggested the role of SIRT3 as a tumor suppressor. It has been reported that SIRT3 induces tumor-suppressing effects such as cell arrest and apoptosis by controlling Bcl-2, p53, hypoxia inducible factor 1 subunit alpha (HIF1α), pyruvate dehydrogenase complex (PDC), superoxide dismutase 2 (SOD2) and glutamic-oxaloacetic transaminase 2 (GOT2)[54-59]. Regarding metastasis, Li

[60] revealed that SIRT3 promoted FOXO3A expression by weakening the Wnt/βcatenin pathway thereby inhibiting EMT and prostate cancer cell migration. Furthermore, Ozden

[61] reported that activation of pyruvate dehydrogenase (PDH) by SIRT3 increased oxidative phosphorylation and reactive oxygen species production and reduced glycolysis which contributed to reduced tumorigenesis in cancer cells.

He drove twice round the city, throwing money to the right and left, and the third time, as he passed under the palace windows, he saw Ludovine lift a corner of the curtain and peep out

Together, we walked down the cement steps, through the long, narrow hall to the infants’ room. They led me to a small room while they went to get the baby. In only a few moments, they were back.

The relationship between SIRT3 expression and the clinical prognosis reportedly differs depending on the type of cancer and no clear consensus has yet been reached[62].

Regarding EC, several reports showed SIRT3 was a tumor promotor in ESCC (Table 2). Cobano?lu

[63] reported that serum SIRT3 Levels were significantly higher in ESCC patients than in the control subjects. Yang

[64] showed that downregulation of SIRT3 induced the proliferation inhibition and apoptosis in ESCC cells. In addition, two articles demonstrated that a high SIRT3 expression was significantly associated with a poor survival outcome[65,66]. There have been no reports yet on the relationship between EAC and SIRT3.

SlRT4

SIRT4 has been reported primarily as a tumor suppressor (Table 1 and Figure 2). Wang

[67] revealed that SIRT4 was downregulated in 30 cancers according to an analysis using data from The Cancer Genome Atlas (TCGA) database. SIRT4 is an important component of the DNA damage response pathway that inhibits glutamine metabolism, arrests the cell cycle and suppresses tumors. When SIRT4 is deficient, glutamine-dependent proliferation and stress-induced genomic instability increase resulting in a tumorigenic phenotype[68]. Csibi

[69] also reported that the mammalian target of rapamycin complex 1 (mTORC1) pathway inhibited SIRT4 and stimulated glutamine metabolism and cell proliferation. In addition, SIRT4 has been reported to enhance E-cadherin and inhibit EMT, thereby decreasing migration and the invasion ability in gastric and colorectal cancer cells[70,71]. Furthermore, Hu

[72] showed that overexpression of SIRT4 induced G1 cell cycle arrest through the inhibition of the phosphorylated extracellular signal-regulated kinases cyclin D and cyclin E. In addition, several studies have revealed that a low SIRT4 expression was significantly correlated with a poor prognosis in patients with various cancers[73].

SIRT2 has been reported to promote cell proliferation in hepatocellular carcinoma (HCC), pancreatic cancer and neuroblastoma[37,38]. SIRT2 also promotes cell growth by interacting with the tumor microenvironment, such as mediating immune evasion and altering the alkaline environment[39]. In cholangiocarcinoma, SIRT2 inhibits apoptosis

the peroxidation reaction through metabolic reprogramming by activating cMYC[40]. In addition, SIRT2 promotes invasion and migration in HCC by stimulating mitochondrial metabolism and mediating EMT[41,42].

The role of SIRT1 in cancer progression is contradictory. This is because SIRT1 can both promote and inhibit tumorigenesis (Table 1 and Figure 2)[7].

SlRT5

As with other sirtuins, the role of SIRT5 in cancer is highly controversial with some reports emphasizing the cancer-promoting function of SIRT5. (Table 1 and Figure 2). SIRT5 functionally activates glutamate dehydrogenase 1 (GLUD1), an important regulator of intracellular glutaminolysis, and is involved in cell proliferation[78]. In addition, Yang reported that SIRT5 mediated the desuccinylation of SHMT2 and enhanced its activity, which in turn promotes serine metabolism in tumor cells thereby promoting cancer cell growth[79]. Furthermore, studies have shown that SIRT3 promotes cell proliferation by targeting NRF2, pyruvate kinase M2 (PKM2), and Sad1 and UNC84 domain containing 2 (SUN2)[80-82]. Regarding apoptosis, SIRT5 has been reported to deacetylate cytochrome C (Cyt c) and induce mitochondrial apoptosis[83]. Gu

[84] demonstrated that SIRT5 enhances autophagy and exerts tumor-promoting functions in gastric cancer cells. Moreover, SIRT5 promotes cancer cell invasion and migration by targeting E2F1[85]. Du

[86] revealed that SIRT5 demalonylated and inactivated succinate dehydrogenase complex flavoprotein subunit A (SDHA) and accumulated its metabolite succinate resulting in resistance to chemotherapy.

They wished themselves back again in the water, and after a month had passed they said it was much more beautiful down below, and pleasanter to be at home

In contrast, SIRT5 has also been reported to have tumor-suppressive effects (Table 1). Chen

[87] revealed that SIRT5-mediated desuccinylation inhibited the activity of acyl-CoA oxidase 1 (ACOX1) and played an important role in the suppression of oxidative stress, protection of the liver and inhibition of HCC development. SIRT5 has been suggested to have a tumor-suppressor function

desuccinylation of superoxide dismutase 1 (SOD1)[88]. Furthermore, Polletta

[89] demonstrated that SIRT5 inhibited ammonia-induced autophagy which is regarded as a protective mechanism for tumor cells. Therefore, activation of SIRT5 is thought to reduce the survival of tumor cells in response to stresses, such as chemotherapy, hypoxia and nutrient starvation.

Several mechanisms that are responsible for the tumor-promoting nature of SIRT1 have been uncovered as follows: (1) SIRT1 contributes to cell proliferation by epigenetically suppressing the expression and activity of many tumor suppressor genes and proteins with DNA damage repair functions such as protein 53 (p53)[8], forkhead class O transcription factor (FOXO) family members[9], E2F transcription factor 1 (E2F1)[10], protein 73 (p73)[11], retinoblastoma protein (RB)[12], Ku70[13], secreted Frizzled-related protein 1(SFRP1), SFRP2, GATA4, GATA5 and mutL homolog 1 (MLH1)[14]; (2) SIRT1 acts as a regulator of apoptosis by deacetylating key apoptosis-related proteins and cell signaling molecules such as p53, nuclear factor kappa B subunit 1 (NF-κB), FOXO3, Ku70, protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and nuclear factor erythroid 2-related factor 2 (NRF2), in response to DNA damage and oxidative stress[6]; and (3) SIRT1 induces epithelial-mesenchymal transition (EMT) and promotes cell migration and metastasis by cooperating with EMT transcription factors such as zinc finger E-box binding homeobox 1 (ZEB1) in prostate cancer[15]. It has also been reported that the high expression of SIRT1 is associated with an advanced stage and poor prognosis in certain types of cancer such as gastric cancer[16], lung adenocarcinoma[17] and colorectal cancer[18].

In EC, there have been no reports on the role of SIRT5, and there is much room for further investigation of the association between SIRT5 and EC.

SlRT6

SIRT6, like other sirtuins, functions as a double-edged sword in cancer (Table 1 and Figure 2). SIRT6 inhibits tumor growth by targeting poly(rC) binding protein 2 (PCBP2) and extracellular signalregulated kinases 1/2 (ERK1/2)[91,92]. SIRT6 represses HIF-1α and regulates the expression of multiple glycolytic genes[93]. This indicates that SIRT6 plays a role in tumor suppression by inhibiting the Warburg effect. In addition, SIRT6 induces apoptosis in cancer cells by acting on NF-κB, BCL2 associated X (Bax) and survivin[94,95]. Bhardwaj

[96] found that SIRT6 inhibited the oncogenic activity of PKM2, which has a non-metabolic nuclear carcinogenic function, resulting in a reduced cell proliferation, migration ability and invasiveness. One meta-analysis revealed that a high SIRT6 expression was associated with a longer OS in gastrointestinal cancers and a favorable TNM stage[97].

One of the future points to be explored concerning sirtuins in EC is expected to be their utility as biomarkers. In most previous studies, the degree of sirtuin expression was assessed by immunohistochemistry. However, the cut-off values for sirtuin expression differed among studies, and this heterogeneity in assessment methods may have led to conflicting results among cancer types. Therefore, more accurate and less-invasive evaluations are anticipated in the future. Serum SIRT3 Levels have been reported to be a potentially useful biomarker, not only in EC[63] but also in lung cancer[111], suggesting that serum sirtuin levels merit exploration as a minimally invasive biomarker. Furthermore, in recent years, a wide variety of public databases, such as TCGA, have been used for analyses[67]. This is expected to make it possible to obtain more comprehensive and standardizable information in the future.

In EC, SIRT6 has been reported as a tumor-promoting factor (Table 2). Huang

[102] demonstrated that SIRT6 was markedly overexpressed in ESCC tissues and that it also promoted cell proliferation and induced the expression of Bcl2, an important anti-apoptotic factor and autophagy in ESCC cells.

SlRT7

Like other sirtuins, SIRT7 has also been reported to have both tumor-promoting and tumor-suppressing roles (Table 1 and Figure 2). SIRT7 promotes cell proliferation by regulating ERK1/2 and histone H3 Lysine 18 acetylation (H3K18ac)[103,104]. In addition, SIRT7 induces apoptosis

miR34a, NF-κB family subunits and the mTOR/insulin like growth factor 2 (IGF2) pathway[105-107]. SIRT7 also influences the metastasis of cancer cells. Yu

[103] showed that cells overexpressing SIRT7 had elevated levels of vimentin and fibronectin, which are markers of mesenchymal lineage, and decreased levels of E-cadherin and β-catenin, which are markers of epithelial lineage indicating enhanced invasion of colon cancer cells.

The role of SIRT7 as a tumor suppressor has been reported to include inhibition of growth and metastasis. Li

[108] demonstrated that SIRT7 inhibited cell proliferation and invasion by deacetylating SMAD4 in oral squamous cell carcinoma. In addition, Tang

[109] also revealed that loss of SIRT7 activated TGF-β signaling and promoted EMT.

The prince was not a little surprised, but he consented to hide himself with Asmund behind the panelling of the room, from where they could see all that went on through a little slit24

Reports concerning the relationship between the SIRT7 expression and the prognosis are conflicting, with some citing a good prognosis while the others describe a poor prognosis[110].

In EC, there are no reports investigating the role of SIRT7, and whether it acts as a tumor-promoting factor or a tumor-suppressing factor remains unclear.

FUTURE PERSPECTlVES

As mentioned above, sirtuins have been investigated in a variety of cancer types and play a dichotomous role depending on the situation. This trend is also true in the field of EC. SIRT1, SIRT2, SIRT3 and SIRT6 have been reported as tumor-promoting factors in ESCC, along with SIRT1 in EAC, while SIRT4 and SIRT2 have been reported as tumor suppressors in ESCC and EAC, respectively. SIRT5 and SIRT7 are interesting targets of study since their roles in both ESCC and EAC have not yet been reported.

In the years to follow, the answers began to arrive, clear and satisfying beyond my most optimistic anticipation21. One of the answers was Enchanted22 Hills, where my nurse friend and I have the privilege of seeing blind children come alive in God’s out-of-doors. Others are the never-ending sources of pleasure and comfort I have found in friendship, in great music, and, most important of all, in my growing belief that as I attune23 my life to divine revelation, I draw closer to God and, through Him, to immortality24.

However, the role of SIRT6 as a tumor-promoting factor has also been reported. SIRT6 enhances HCC cell proliferation and inhibits apoptosis through the regulation of the ERK1/2 pathway[98]. In addition, Zhou

[99] revealed that SIRT6 inhibited the acetylation of AKT and promoted its activation thereby preventing apoptosis and inducing cell proliferation. Bai

[100] reported that the overexpression of SIRT6 in non-small-cell lung cancer cell lines promoted migration and invasion

ERK1/2/MMP9 signaling. SIRT6 has also been reported to positively regulate autophagy in melanoma cells and to exhibit tumor-promoting effects[101].

Since sirtuin enzymes play an important role in the regulation of various cellular events, there is strong interest in pursuing sirtuins as therapeutic targets. Although many reports related to the development of sirtuin inhibitors/activators have been found in electronic searches, only a very limited number of small-molecule compounds, such as reveratol and Ex-527, have been subjected to clinical trials[112]. In the field of EC, the effects of the SIRT1 inhibitors rapamycin and sirtinol have been reported

and

[35,36]. However, SIRT1, like other sirtuins, has been suggested to promote or inhibit cancer in a context-dependent manner so many comprehensive studies are needed to determine its clinical application. Although not yet presented, other sirtuin-targeted agents still have great therapeutic potential and advances in this area will contribute to the development of EC treatment.

O wealth of my life and source of my joy! responded Dil-aram, I do not know what the rose did to the cypress; but so much I know that the person who told Mihr-afruz about it is a negro whom she hides under her throne

In recent years, the breakthrough of immunotherapy has been considered an important topic in EC[113]. The involvement of sirtuins in immunity has been widely studied since the early discovery that SIRT1 regulates NF-κB, a transcription factor known to control inflammation and immune cell proliferation[114]. There have been no reports on the role of sirtuins in immunotherapy of esophageal cancer, although some reports have appeared in other cancer types. Zhang

[115] showed that pharmacological inhibition of SIRT2 increased natural killer cell infiltration into the tumor and suppressed tumor growth in allograft melanoma. Furthermore, Xiang

[116] demonstrated that SIRT7 suppressed myocyte enhancer factor 2D acetylation and programmed death ligand 1 expression and promoted HCC cell proliferation. Thus, the role of sirtuins in anti-tumor immunity in EC is an issue that deserves further attention and research.

CONCLUSlON

In summary, sirtuins may be a key target for EC treatment in the future. However, much research is still needed to determine the clinical application as many aspects remain unresolved. We hope that this review will contribute to the development of this field.

FOOTNOTES

Otsuka R contributed to conception and design; All authors contributed to manuscript writing, figure preparation and review and approval of the article to be published.

The authors declare that they have no conflict of interest.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Japan

Ryota Otsuka 0000-0001-7360-9069; Koichi Hayano 0000-0003-4733-8220; Hisahiro Matsubara 0000-0002-2335-4704.

The Fairy refused at first with a great show of firmness, but who could resist the tears and entreaties21 of anyone so pretty as Placida? It came to this in the end, that she transported the Princess just as she was, cosily22 tucked up upon her favourite couch, to her own Grotto23, and this new disappearance left all the people in despair, and Gridelin went about looking more distracted than ever

Gong ZM

Many nights, after I’d tucked my own children into bed, I’d sit and think about Ronny. Where was he? Was he safe? Was he reading a book by flashlight under the blan-kets? Did he even have blankets?

Filipodia

Gong ZM

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