Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis

Yu Muta, Juan F. Linares, Anxo Martinez-Ordoñez, Angeles Duran, Tania Cid-Diaz, Hiroto Kinoshita, Xiao Zhang, Qixiu Han, Yuki Nakanishi, Naoko Nakanishi, Thekla Cordes, Gurpreet K. Arora, Marc Ruiz-Martinez, Miguel Reina-Campos, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Christian M. Metallo, Timothy F. Osborne, Maria T. Diaz-Meco () and Jorge Moscat ()
Additional contact information
Yu Muta: Weill Cornell Medicine
Juan F. Linares: Weill Cornell Medicine
Anxo Martinez-Ordoñez: Weill Cornell Medicine
Angeles Duran: Weill Cornell Medicine
Tania Cid-Diaz: Weill Cornell Medicine
Hiroto Kinoshita: Weill Cornell Medicine
Xiao Zhang: Weill Cornell Medicine
Qixiu Han: Weill Cornell Medicine
Yuki Nakanishi: Kyoto University Graduate School of Medicine
Naoko Nakanishi: Kyoto Prefectural University of Medicine
Thekla Cordes: Salk Institute for Biological Studies
Gurpreet K. Arora: Sanford Burnham Prebys
Marc Ruiz-Martinez: Weill Cornell Medicine
Miguel Reina-Campos: University of California San Diego
Hiroaki Kasashima: Osaka Metropolitan University Graduate School of Medicine
Masakazu Yashiro: Osaka Metropolitan University Graduate School of Medicine
Kiyoshi Maeda: Osaka Metropolitan University Graduate School of Medicine
Ana Albaladejo-Gonzalez: Universidad Católica de Murcia (UCAM)
Daniel Torres-Moreno: Universidad Católica de Murcia (UCAM)
José García-Solano: Universidad Católica de Murcia (UCAM)
Pablo Conesa-Zamora: Universidad Católica de Murcia (UCAM)
Giorgio Inghirami: Weill Cornell Medicine
Christian M. Metallo: Salk Institute for Biological Studies
Timothy F. Osborne: Johns Hopkins All Children’s Hospital, St
Maria T. Diaz-Meco: Weill Cornell Medicine
Jorge Moscat: Weill Cornell Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The 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.

Date: 2023
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DOI: 10.1038/s41467-023-43690-5

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