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.
|Journal||Biochimica et Biophysica Acta - Molecular Cell Research|
|State||Published - Apr 2021|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health [grant numbers R01 DK048498 and P30 CA177558 to BME].
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].
© 2021 Elsevier B.V.
- Cell differentiation
- Cell signaling
- Protein expression
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology