Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer

Elke Wauters, Victor J. Sanchez-Arevalo Lobo, Andreia V. Pinho, Amanda Mawson, Daniel Herranz, Jianmin Wu, Mark J. Cowley, Emily K. Colvin, Erna Ngwayi Njicop, Rob L. Sutherland, Tao Liu, Manuel Serrano, Luc Bouwens, Francisco X. Real, Andrew V. Biankin, Ilse Rooman

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-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-to-cytoplasmic 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 β-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 β-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.

LanguageEnglish
Pages2357-2367
Number of pages11
JournalCancer Research
Volume73
Issue number7
DOIs
Publication statusPublished - 1 Apr 2013
Externally publishedYes

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Sirtuin 1
Metaplasia
Pancreatic Neoplasms
Cell Survival
Neoplasms
Adenocarcinoma
Carcinogenesis
beta Catenin
Sirtuin 2
Exocrine Pancreas
Acinar Cells

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Wauters, E., Sanchez-Arevalo Lobo, V. J., Pinho, A. V., Mawson, A., Herranz, D., Wu, J., ... Rooman, I. (2013). Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer. Cancer Research, 73(7), 2357-2367. https://doi.org/10.1158/0008-5472.CAN-12-3359
Wauters, Elke ; Sanchez-Arevalo Lobo, Victor J. ; Pinho, Andreia V. ; Mawson, Amanda ; Herranz, Daniel ; Wu, Jianmin ; Cowley, Mark J. ; Colvin, Emily K. ; Njicop, Erna Ngwayi ; Sutherland, Rob L. ; Liu, Tao ; Serrano, Manuel ; Bouwens, Luc ; Real, Francisco X. ; Biankin, Andrew V. ; Rooman, Ilse. / Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer. In: Cancer Research. 2013 ; Vol. 73, No. 7. pp. 2357-2367.
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abstract = "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-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-to-cytoplasmic 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 β-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 β-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.",
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Wauters, E, Sanchez-Arevalo Lobo, VJ, Pinho, AV, Mawson, A, Herranz, D, Wu, J, Cowley, MJ, Colvin, EK, Njicop, EN, Sutherland, RL, Liu, T, Serrano, M, Bouwens, L, Real, FX, Biankin, AV & Rooman, I 2013, 'Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer', Cancer Research, vol. 73, no. 7, pp. 2357-2367. https://doi.org/10.1158/0008-5472.CAN-12-3359

Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer. / Wauters, Elke; Sanchez-Arevalo Lobo, Victor J.; Pinho, Andreia V.; Mawson, Amanda; Herranz, Daniel; Wu, Jianmin; Cowley, Mark J.; Colvin, Emily K.; Njicop, Erna Ngwayi; Sutherland, Rob L.; Liu, Tao; Serrano, Manuel; Bouwens, Luc; Real, Francisco X.; Biankin, Andrew V.; Rooman, Ilse.

In: Cancer Research, Vol. 73, No. 7, 01.04.2013, p. 2357-2367.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Wauters, Elke

AU - Sanchez-Arevalo Lobo, Victor J.

AU - Pinho, Andreia V.

AU - Mawson, Amanda

AU - Herranz, Daniel

AU - Wu, Jianmin

AU - Cowley, Mark J.

AU - Colvin, Emily K.

AU - Njicop, Erna Ngwayi

AU - Sutherland, Rob L.

AU - Liu, Tao

AU - Serrano, Manuel

AU - Bouwens, Luc

AU - Real, Francisco X.

AU - Biankin, Andrew V.

AU - Rooman, Ilse

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N2 - 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-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-to-cytoplasmic 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 β-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 β-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.

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