SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummary
Background and Aims: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetyl...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20300047 |
| _version_ | 1819061580901384192 |
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| author | Chang Li Yuning Zhou Piotr Rychahou Heidi L. Weiss Eun Y. Lee Courtney L. Perry Terrence A. Barrett Qingding Wang B. Mark Evers |
| author_facet | Chang Li Yuning Zhou Piotr Rychahou Heidi L. Weiss Eun Y. Lee Courtney L. Perry Terrence A. Barrett Qingding Wang B. Mark Evers |
| author_sort | Chang Li |
| collection | DOAJ |
| description | Background and Aims: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis. Methods: IECs were collected from SIRT2-deficient mice and patients with IBD. Expression of SIRT2, differentiation markers (mucin2, intestinal alkaline phosphatase, villin, Na,K-ATPase, and lysozyme) and Wnt target genes (EPHB2, AXIN2, and cyclin D1) was determined by western blot, real-time RT-PCR, or immunohistochemical (IHC) staining. IECs were treated with TNF or transfected with siRNA targeting SIRT2. Proliferation was determined by villus height and crypt depth, and Ki67 and cyclin D1 IHC staining. For studies using organoids, intestinal crypts were isolated. Results: Increased SIRT2 expression was localized to the more differentiated region of the intestine. In contrast, SIRT2 deficiency impaired proliferation and differentiation and altered stemness in the small intestinal epithelium ex vivo and in vivo. SIRT2-deficient mice showed decreased intestinal enterocyte and goblet cell differentiation but increased the Paneth cell lineage and increased proliferation of IECs. Moreover, we found that SIRT2 inhibits Wnt/β-catenin signaling, which critically regulates IEC proliferation and differentiation. Consistent with a distinct role for SIRT2 in maintenance of gut homeostasis, intestinal mucosa from IBD patients exhibited decreased SIRT2 expression. Conclusion: We demonstrate that SIRT2, which is decreased in intestinal tissues from IBD patients, regulates Wnt-β-catenin signaling and is important for maintenance of IEC proliferation and differentiation. |
| first_indexed | 2024-12-21T14:45:09Z |
| format | Article |
| id | doaj.art-4ec9fb47344648e8968bcf4cb061c8c6 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-21T14:45:09Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-4ec9fb47344648e8968bcf4cb061c8c62022-12-21T19:00:02ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-011014357SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummaryChang Li0Yuning Zhou1Piotr Rychahou2Heidi L. Weiss3Eun Y. Lee4Courtney L. Perry5Terrence A. Barrett6Qingding Wang7B. Mark Evers8Markey Cancer Center, University of Kentucky, Lexington, KentuckyMarkey Cancer Center, University of Kentucky, Lexington, KentuckyMarkey Cancer Center, University of Kentucky, Lexington, Kentucky; Department of Surgery, University of Kentucky, Lexington, KentuckyMarkey Cancer Center, University of Kentucky, Lexington, KentuckyMarkey Cancer Center, University of Kentucky, Lexington, Kentucky; Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KentuckyDepartment of Internal Medicine, University of Kentucky, Lexington, KentuckyDepartment of Internal Medicine, University of Kentucky, Lexington, KentuckyMarkey Cancer Center, University of Kentucky, Lexington, Kentucky; Department of Surgery, University of Kentucky, Lexington, Kentucky; Qingding Wang, PhD, Markey Cancer Center, University of Kentucky, 800 Rose Street, CC140, Lexington, KY 40536-0293. fax: (859) 323-2074.Markey Cancer Center, University of Kentucky, Lexington, Kentucky; Department of Surgery, University of Kentucky, Lexington, Kentucky; Correspondence Address correspondence to: B. Mark Evers, MD, Markey Cancer Center, University of Kentucky, 800 Rose Street, CC140, Lexington, KY 40536-0293. fax: (859) 323-2074.Background and Aims: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis. Methods: IECs were collected from SIRT2-deficient mice and patients with IBD. Expression of SIRT2, differentiation markers (mucin2, intestinal alkaline phosphatase, villin, Na,K-ATPase, and lysozyme) and Wnt target genes (EPHB2, AXIN2, and cyclin D1) was determined by western blot, real-time RT-PCR, or immunohistochemical (IHC) staining. IECs were treated with TNF or transfected with siRNA targeting SIRT2. Proliferation was determined by villus height and crypt depth, and Ki67 and cyclin D1 IHC staining. For studies using organoids, intestinal crypts were isolated. Results: Increased SIRT2 expression was localized to the more differentiated region of the intestine. In contrast, SIRT2 deficiency impaired proliferation and differentiation and altered stemness in the small intestinal epithelium ex vivo and in vivo. SIRT2-deficient mice showed decreased intestinal enterocyte and goblet cell differentiation but increased the Paneth cell lineage and increased proliferation of IECs. Moreover, we found that SIRT2 inhibits Wnt/β-catenin signaling, which critically regulates IEC proliferation and differentiation. Consistent with a distinct role for SIRT2 in maintenance of gut homeostasis, intestinal mucosa from IBD patients exhibited decreased SIRT2 expression. Conclusion: We demonstrate that SIRT2, which is decreased in intestinal tissues from IBD patients, regulates Wnt-β-catenin signaling and is important for maintenance of IEC proliferation and differentiation.http://www.sciencedirect.com/science/article/pii/S2352345X20300047SirtuinIECIntestinal Epithelial CellsWnt/β-CateninIntestinal HomeostasisMouse Model |
| spellingShingle | Chang Li Yuning Zhou Piotr Rychahou Heidi L. Weiss Eun Y. Lee Courtney L. Perry Terrence A. Barrett Qingding Wang B. Mark Evers SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummary Cellular and Molecular Gastroenterology and Hepatology Sirtuin IEC Intestinal Epithelial Cells Wnt/β-Catenin Intestinal Homeostasis Mouse Model |
| title | SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummary |
| title_full | SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummary |
| title_fullStr | SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummary |
| title_full_unstemmed | SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummary |
| title_short | SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and DifferentiationSummary |
| title_sort | sirt2 contributes to the regulation of intestinal cell proliferation and differentiationsummary |
| topic | Sirtuin IEC Intestinal Epithelial Cells Wnt/β-Catenin Intestinal Homeostasis Mouse Model |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X20300047 |
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