Janus‐faced role of SIRT1 in tumorigenesis

Song, Na‐Young; Surh, Young‐Joon

doi:10.1111/j.1749-6632.2012.06762.x

Cited by 132 publications

(108 citation statements)

References 98 publications

(312 reference statements)

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“…Its deacetylation activity enables it to interact with a variety of important transcription factors and transcriptional co-regulatory factors, to regulate gene transcription, chromosome stability and activity of target proteins, which are involved in tumor metabolism and development (5,6). The current results demonstrated that SIRT1 plays a dual role as a tumor promoter as well as a tumor suppressor (7). Its involvement in tumorigenesis may be due to its diverse distribution in different tissues and different upstream and downstream regulatory factors that regulate its function (8).…”

Section: Introductionmentioning

confidence: 74%

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Zheng

Qiu

et al. 2014

Oncology Reports

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Abstract. Silent information regulator 1 (SIRT1) is involved in a number of cellular regulatory mechanisms affecting cellular life span, stress resistance, apoptosis and cellular metabolism. Recent studies have revealed that SIRT1 plays a dual role as a tumor suppressor and a tumor promoter in multiple stages of carcinogenesis. Increased lipogenesis has been found in cancer cells, sterol regulatory element binding protein 1 (SREBP1) are nuclear lipogenic transcription factors, which mainly regulate lipogenic processes by activating genes involved in fatty acid and triglyceride biosynthesis. In the present study, we detected expression of SIRT1 in endometrial cancer (EC) and illustrated the relationship between SIRT1 and SREBP1, which indicated that SIRT1 could stimulate endometrial tumor growth through the lipogenic pathway. Gene expression levels of SIRT1 were assayed using quantitative real-time PCR and protein expression levels were detected by western blotting. RNA interference was conducted in order to explore the subsequent effect on tumor cells and on the expression of SREBP1. Expression levels of SIRT1 in EC were found to be significantly higher than in normal endometrium. Knockdown of SIRT1 could downregulate expression of SREBP1 and suppress cell proliferation. These results demonstrated that SIRT1 may play a role as a tumor promoter in EC and can promote endometrial tumor growth by promoting lipogenesis. Our findings suggest that targeting SIRT1 may provide a theoretical basis for the management of EC. IntroductionEndometrial cancer (EC) is the most common malignancy of the female reproductive tract and its incidence is on the increase (1). Approximately 40% of all cases can be attributed to obesity (2). Aberration in lipid metabolism contributes to different aspects of tumorigenesis (3); our research team focused on this domain of EC in recent years.NAD-dependent class III histone deacetylase silent information regulator 1 (SIRT1), that shares the highest degree of homology with the yeast protein SIR2, can deacetylate both histones and non-histone proteins (4). Its deacetylation activity enables it to interact with a variety of important transcription factors and transcriptional co-regulatory factors, to regulate gene transcription, chromosome stability and activity of target proteins, which are involved in tumor metabolism and development (5,6). The current results demonstrated that SIRT1 plays a dual role as a tumor promoter as well as a tumor suppressor (7). Its involvement in tumorigenesis may be due to its diverse distribution in different tissues and different upstream and downstream regulatory factors that regulate its function (8).Sterol regulatory element binding protein 1 (SREBP1) belongs to the family of the basic helix-loop-helix leucine zipper family of DNA binding transcription factors, which can regulate most enzymes involved in fatty acid biosynthesis, such as acetyl-CoA carboxylase, fatty acid synthase, Elovl-6 and stearoyl-CoA desaturase (9). Lipogenesis is increased in cancer cells...

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Section: Introductionmentioning

confidence: 74%

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Zheng

Qiu

et al. 2014

Oncology Reports

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“…Furthermore, altered intracellular localization likely changes the interactions with target proteins. Other studies have shown that intracellular Sirt1 localization changes in response to physiologic and pathologic stimuli resulting in altered cell differentiation and different roles during multistage carcinogenesis (22,36,37). The functional impact of these changes in Sirt1 in pancreas was explored in this study.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

et al. 2013

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The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD þ -dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-tocytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and b-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of b-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. Cancer Res; 73(7); 2357-67. Ó2012 AACR.

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“…Besides these Janus-faced roles in cancer promotion, SIRT1 might determine tumor responses to anticancer drugs. Although SIRT1 has not been intensively explored in terms of cancer chemotherapy, previous studies have supported the notion that SIRT1 plays some positive roles in tumor acquisition of chemoresistance (19). Whether SIRT1 participates in the hypoxia-induced chemoresistance is unclear.…”

Section: Introductionmentioning

confidence: 99%

SIRT1 and AMPK Mediate Hypoxia-Induced Resistance of Non–Small Cell Lung Cancers to Cisplatin and Doxorubicin

2014

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SIRT1 is an NAD þ -dependent protein deacetylase induced by metabolic stresses, such as nutrition or oxygen deprivation. Although SIRT1 contributes to aging and metabolic disorders, its role in cancer progression and therapeutic responses remains controversial. Because hypoxia occurs widely in solid tumors, where it provokes drug resistance, we investigated the involvement of SIRT1 in hypoxia-induced chemoresistance. SIRT1 was downregulated in a panel of non-small cell lung carcinoma (NSCLC) cells exposed to hypoxia for 48 hours. The master metabolic kinase AMP-activated protein kinase (AMPK) was inactivated under the same conditions, likely due to attenuation of the SIRT1/LKB1-mediated AMPK activation process. Notably, hypoxic inactivation of this SIRT1-AMPK pathway led to cisplatin and doxorubicin resistance. Mechanistic investigations suggested that this pathway supported the cytotoxic response to cisplatin and doxorubicin by licensing an apoptotic process controlled by mitochondria. We confirmed the involvement of this pathway in a mouse xenograft model of human NSCLC. Furthermore, we demonstrated that a SIRT1 activator SRT1720 augmented the antitumor effects of cisplatin, and these effects could be blocked by administration of an AMPK inhibitor compound C. Taken together, our results offer preclinical proof-of-concept to target the SIRT1-AMPK pathway as a strategy to overcome hypoxia-induced chemoresistance in NSCLC. Cancer Res; 74(1); 298-308. Ó2013 AACR.

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Janus‐faced role of SIRT1 in tumorigenesis

Cited by 132 publications

References 98 publications

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

SIRT1 and AMPK Mediate Hypoxia-Induced Resistance of Non–Small Cell Lung Cancers to Cisplatin and Doxorubicin

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