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

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dc.contributor.authorSoo Young Jun-
dc.contributor.authorA J Brown-
dc.contributor.authorN K Chua-
dc.contributor.authorJi Yong Yoon-
dc.contributor.authorJeong Ju Lee-
dc.contributor.authorJin Ok Yang-
dc.contributor.authorIn Su Jang-
dc.contributor.authorSu Jin Jeon-
dc.contributor.authorT I Choi-
dc.contributor.authorC H Kim-
dc.contributor.authorNam-Soon Kim-
dc.date.accessioned2021-03-12T01:02:17Z-
dc.date.available2021-03-12T01:02:17Z-
dc.date.issued2021-
dc.identifier.issn00165085-
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/24175-
dc.description.abstractBackground & 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.-
dc.publisherElsevier-
dc.titleReduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis-
dc.title.alternativeReduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis-
dc.typeArticle-
dc.citation.titleGastroenterology-
dc.citation.number4-
dc.citation.endPage1207-
dc.citation.startPage1194-
dc.citation.volume160-
dc.contributor.affiliatedAuthorSoo Young Jun-
dc.contributor.affiliatedAuthorJi Yong Yoon-
dc.contributor.affiliatedAuthorJeong Ju Lee-
dc.contributor.affiliatedAuthorJin Ok Yang-
dc.contributor.affiliatedAuthorIn Su Jang-
dc.contributor.affiliatedAuthorSu Jin Jeon-
dc.contributor.affiliatedAuthorNam-Soon Kim-
dc.contributor.alternativeName전수영-
dc.contributor.alternativeNameBrown-
dc.contributor.alternativeNameChua-
dc.contributor.alternativeName윤지용-
dc.contributor.alternativeName이정주-
dc.contributor.alternativeName양진옥-
dc.contributor.alternativeName장인수-
dc.contributor.alternativeName전수진-
dc.contributor.alternativeName최태익-
dc.contributor.alternativeName김철희-
dc.contributor.alternativeName김남순-
dc.identifier.bibliographicCitationGastroenterology, vol. 160, no. 4, pp. 1194-1207-
dc.identifier.doi10.1053/j.gastro.2020.09.009-
dc.subject.keywordColon Cancer Development-
dc.subject.keywordLipoproteins-
dc.subject.keywordMevalonate Pathway-
dc.subject.keywordCancer Stem Cells-
dc.subject.localLipoproteins-
dc.subject.localLipoprotein-
dc.description.journalClassY-
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
Korea Bioinformation Center > 1. Journal Articles
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