Dmitrieva-Posocco, Oxana, Wong, Andrea C, Lundgren, Patrick, Golos, Aleksandra M, Descamps, Hélène C, Dohnalová, Lenka, Cramer, Zvi, Tian, Yuhua, Yueh, Brian, Eskiocak, Onur, Egervari, Gabor, Lan, Yemin, Liu, Jinping, Fan, Jiaxin, Kim, Jihee, Madhu, Bhoomi, Schneider, Kai Markus, Khoziainova, Svetlana, Andreeva, Natalia, Wang, Qiaohong, Li, Ning, Furth, Emma E, Bailis, Will, Kelsen, Judith R, Hamilton, Kathryn E, Kaestner, Klaus H, Berger, Shelley L, Epstein, Jonathan A, Jain, Rajan, Li, Mingyao, Beyaz, Semir, Lengner, Christopher J, Katona, Bryson W, Grivennikov, Sergei I, Thaiss, Christoph A, Levy, Maayan (April 2022) β-Hydroxybutyrate suppresses colorectal cancer. Nature, 605 (7908). pp. 160-165. ISSN 0028-0836
Abstract
Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.
| Item Type: | Paper |
|---|---|
| Subjects: | Investigative techniques and equipment > cell culture > cancer organoids Investigative techniques and equipment > assays > RNA-seq Investigative techniques and equipment > assays > Single cell sequencing |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program CSHL labs > Beyaz lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 27 April 2022 |
| Date Deposited: | 04 May 2022 13:24 |
| Last Modified: | 02 May 2024 13:52 |
| PMCID: | PMC9448510 |
| URI: | https://repository.cshl.edu/id/eprint/40601 |
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