Regulation of SIRT2 by Wnt/β-catenin signaling pathway in colorectal cancer cells

Chang Li; Yuning Zhou; Ji Tae Kim; Tomoko Sengoku; Michael C. Alstott; Heidi L. Weiss; Qingding Wang; B. Mark Evers

doi:10.1016/j.bbamcr.2021.118966

Regulation of SIRT2 by Wnt/β-catenin signaling pathway in colorectal cancer cells

Chang Li, Yuning Zhou, Ji Tae Kim, Tomoko Sengoku, Michael C. Alstott, Heidi L. Weiss, Qingding Wang, B. Mark Evers

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Activation of the Wnt/β-catenin pathway is one of the hallmarks of colorectal cancer (CRC). Sirtuin 2 (SIRT2) protein has been shown to inhibit CRC proliferation. Previously, we reported that SIRT2 plays an important role in the maintenance of normal intestinal cell homeostasis. Here, we show that SIRT2 is a direct target gene of Wnt/β-catenin signaling in CRC cells. Inhibition or knockdown of Wnt/β-catenin increased SIRT2 promoter activity and mRNA and protein expression, whereas activation of Wnt/β-catenin decreased SIRT2 promoter activity and expression. β-Catenin was recruited to the promoter of SIRT2 and transcriptionally regulated SIRT2 expression. Wnt/β-catenin inhibition increased mitochondrial oxidative phosphorylation (OXPHOS) and CRC cell differentiation. Moreover, inhibition of OXPHOS attenuated the differentiation of CRC cells induced by Wnt/β-catenin inhibition. In contrast, inhibition or knockdown of SIRT2 decreased, while overexpression of SIRT2 increased, OXPHOS activity and differentiation in CRC cells. Consistently, inhibition or knockdown or SIRT2 attenuated the differentiation induced by Wnt/β-catenin inhibition. These results demonstrate that SIRT2 is a novel target gene of the Wnt/β-catenin signaling and contributes to the differentiation of CRC cells.

Original language	English
Article number	118966
Journal	Biochimica et Biophysica Acta - Molecular Cell Research
Volume	1868
Issue number	4
DOIs	https://doi.org/10.1016/j.bbamcr.2021.118966
State	Published - Apr 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health [grant numbers R01 DK048498 and P30 CA177558 to BME].

Funding Information:
The authors thank Donna Gilbreath for manuscript preparation; the Redox Metabolism, and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center. This work was supported by the National Institutes of Health [grant numbers R01 DK048498 and P30 CA177558 to BME].

Publisher Copyright:
© 2021 Elsevier B.V.

Keywords

Cell differentiation
Cell signaling
Protein expression

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbamcr.2021.118966

Cite this

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title = "Regulation of SIRT2 by Wnt/β-catenin signaling pathway in colorectal cancer cells",

abstract = "Activation of the Wnt/β-catenin pathway is one of the hallmarks of colorectal cancer (CRC). Sirtuin 2 (SIRT2) protein has been shown to inhibit CRC proliferation. Previously, we reported that SIRT2 plays an important role in the maintenance of normal intestinal cell homeostasis. Here, we show that SIRT2 is a direct target gene of Wnt/β-catenin signaling in CRC cells. Inhibition or knockdown of Wnt/β-catenin increased SIRT2 promoter activity and mRNA and protein expression, whereas activation of Wnt/β-catenin decreased SIRT2 promoter activity and expression. β-Catenin was recruited to the promoter of SIRT2 and transcriptionally regulated SIRT2 expression. Wnt/β-catenin inhibition increased mitochondrial oxidative phosphorylation (OXPHOS) and CRC cell differentiation. Moreover, inhibition of OXPHOS attenuated the differentiation of CRC cells induced by Wnt/β-catenin inhibition. In contrast, inhibition or knockdown of SIRT2 decreased, while overexpression of SIRT2 increased, OXPHOS activity and differentiation in CRC cells. Consistently, inhibition or knockdown or SIRT2 attenuated the differentiation induced by Wnt/β-catenin inhibition. These results demonstrate that SIRT2 is a novel target gene of the Wnt/β-catenin signaling and contributes to the differentiation of CRC cells.",

keywords = "Cell differentiation, Cell signaling, Protein expression",

author = "Chang Li and Yuning Zhou and Kim, {Ji Tae} and Tomoko Sengoku and Alstott, {Michael C.} and Weiss, {Heidi L.} and Qingding Wang and Evers, {B. Mark}",

note = "Funding Information: This work was supported by the National Institutes of Health [grant numbers R01 DK048498 and P30 CA177558 to BME]. Funding Information: The authors thank Donna Gilbreath for manuscript preparation; the Redox Metabolism, and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center. This work was supported by the National Institutes of Health [grant numbers R01 DK048498 and P30 CA177558 to BME]. Publisher Copyright: {\textcopyright} 2021 Elsevier B.V.",

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AU - Alstott, Michael C.

AU - Weiss, Heidi L.

AU - Wang, Qingding

AU - Evers, B. Mark

N1 - Funding Information: This work was supported by the National Institutes of Health [grant numbers R01 DK048498 and P30 CA177558 to BME]. Funding Information: The authors thank Donna Gilbreath for manuscript preparation; the Redox Metabolism, and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center. This work was supported by the National Institutes of Health [grant numbers R01 DK048498 and P30 CA177558 to BME]. Publisher Copyright: © 2021 Elsevier B.V.

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N2 - Activation of the Wnt/β-catenin pathway is one of the hallmarks of colorectal cancer (CRC). Sirtuin 2 (SIRT2) protein has been shown to inhibit CRC proliferation. Previously, we reported that SIRT2 plays an important role in the maintenance of normal intestinal cell homeostasis. Here, we show that SIRT2 is a direct target gene of Wnt/β-catenin signaling in CRC cells. Inhibition or knockdown of Wnt/β-catenin increased SIRT2 promoter activity and mRNA and protein expression, whereas activation of Wnt/β-catenin decreased SIRT2 promoter activity and expression. β-Catenin was recruited to the promoter of SIRT2 and transcriptionally regulated SIRT2 expression. Wnt/β-catenin inhibition increased mitochondrial oxidative phosphorylation (OXPHOS) and CRC cell differentiation. Moreover, inhibition of OXPHOS attenuated the differentiation of CRC cells induced by Wnt/β-catenin inhibition. In contrast, inhibition or knockdown of SIRT2 decreased, while overexpression of SIRT2 increased, OXPHOS activity and differentiation in CRC cells. Consistently, inhibition or knockdown or SIRT2 attenuated the differentiation induced by Wnt/β-catenin inhibition. These results demonstrate that SIRT2 is a novel target gene of the Wnt/β-catenin signaling and contributes to the differentiation of CRC cells.

AB - Activation of the Wnt/β-catenin pathway is one of the hallmarks of colorectal cancer (CRC). Sirtuin 2 (SIRT2) protein has been shown to inhibit CRC proliferation. Previously, we reported that SIRT2 plays an important role in the maintenance of normal intestinal cell homeostasis. Here, we show that SIRT2 is a direct target gene of Wnt/β-catenin signaling in CRC cells. Inhibition or knockdown of Wnt/β-catenin increased SIRT2 promoter activity and mRNA and protein expression, whereas activation of Wnt/β-catenin decreased SIRT2 promoter activity and expression. β-Catenin was recruited to the promoter of SIRT2 and transcriptionally regulated SIRT2 expression. Wnt/β-catenin inhibition increased mitochondrial oxidative phosphorylation (OXPHOS) and CRC cell differentiation. Moreover, inhibition of OXPHOS attenuated the differentiation of CRC cells induced by Wnt/β-catenin inhibition. In contrast, inhibition or knockdown of SIRT2 decreased, while overexpression of SIRT2 increased, OXPHOS activity and differentiation in CRC cells. Consistently, inhibition or knockdown or SIRT2 attenuated the differentiation induced by Wnt/β-catenin inhibition. These results demonstrate that SIRT2 is a novel target gene of the Wnt/β-catenin signaling and contributes to the differentiation of CRC cells.

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Regulation of SIRT2 by Wnt/β-catenin signaling pathway in colorectal cancer cells

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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