Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis
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Published:2023-12-13
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Muta YuORCID, Linares Juan F., Martinez-Ordoñez Anxo, Duran Angeles, Cid-Diaz Tania, Kinoshita HirotoORCID, Zhang Xiao, Han Qixiu, Nakanishi YukiORCID, Nakanishi Naoko, Cordes TheklaORCID, Arora Gurpreet K., Ruiz-Martinez MarcORCID, Reina-Campos MiguelORCID, Kasashima HiroakiORCID, Yashiro Masakazu, Maeda Kiyoshi, Albaladejo-Gonzalez Ana, Torres-Moreno Daniel, García-Solano José, Conesa-Zamora PabloORCID, Inghirami GiorgioORCID, Metallo Christian M.ORCID, Osborne Timothy F.ORCID, Diaz-Meco Maria T.ORCID, Moscat JorgeORCID
Abstract
AbstractThe metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
Funder
Foundation for the National Institutes of Health Japan Society for the Promotion of Science London
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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