Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis

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Title
Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis
Author(s)
Soo Young Jun; A J Brown; N K Chua; Ji Yong YoonJeong Ju LeeJin Ok YangIn Su Jang; Su Jin Jeon; T I Choi; C H Kim; Nam-Soon Kim
Bibliographic Citation
Gastroenterology, vol. 160, no. 4, pp. 1194-1207
Publication Year
2021
Abstract
Background & aims: Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is suggested as a proto-oncogene. Paradoxically, SQLE is degraded by excess cholesterol, and low SQLE is associated with aggressive colorectal cancer (CRC). Therefore, we studied the functional consequences of SQLE reduction in CRC progression. Methods: Gene and protein expression data and clinical features of CRCs were obtained from public databases and 293 human tissues, analyzed by immunohistochemistry. In vitro studies showed underlying mechanisms of CRC progression mediated by SQLE reduction. Mice were fed a 2% high-cholesterol or a control diet before and after cecum implantation of SQLE genetic knockdown/control CRC cells. Metastatic dissemination and circulating cancer stem cells were demonstrated by in vivo tracking and flow cytometry analysis, respectively. Results: In vitro studies showed that SQLE reduction helped cancer cells overcome constraints by inducing the epithelial-mesenchymal transition required to generate cancer stem cells. Surprisingly, SQLE interacted with GSK3β and p53. Active GSK3β contributes to the stability of SQLE, thereby increasing cell cholesterol content, whereas SQLE depletion disrupted the GSK3β/p53 complex, resulting in a metastatic phenotype. This was confirmed in a spontaneous CRC metastasis mice model, where SQLE reduction, by a high-cholesterol regimen or genetic knockdown, strikingly promoted CRC aggressiveness through the production of migratory cancer stem cells. Conclusions: We showed that SQLE reduction caused by cholesterol accumulation aggravates CRC progression via the activation of the β-catenin oncogenic pathway and deactivation of the p53 tumor suppressor pathway. Our findings provide new insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC aggressiveness and a prognostic biomarker.
Keyword
Colon Cancer DevelopmentLipoproteinsMevalonate PathwayCancer Stem Cells
ISSN
0016-5085
Publisher
Elsevier
DOI
http://dx.doi.org/10.1053/j.gastro.2020.09.009
Type
Article
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
Korea Bioinformation Center > 1. Journal Articles
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