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β-Hydroxybutyrate suppresses colorectal cancer
Oxana Dmitrieva-Posocco1, Andrea C Wong1, Patrick Lundgren1
1Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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.
Insights
Ketogenic diets and beta-hydroxybutyrate (BHB) inhibit colorectal cancer (CRC) growth by activating the Hopx pathway. This metabolite pathway offers new strategies for CRC prevention and therapy.
Area of Science:
- Oncology
- Metabolism
- Molecular Biology
Background:
- Colorectal cancer (CRC) is a leading cause of cancer worldwide, necessitating novel prevention and therapeutic strategies.
- Existing treatments for CRC can be limited by side effects and efficacy.
Purpose of the Study:
- To identify metabolite signaling pathways that can inhibit colorectal cancer growth.
- To investigate the role of ketogenic diets and ketone bodies in CRC progression.
Main Methods:
- Dietary screening in autochthonous animal models of colorectal cancer.
- Investigating the effects of beta-hydroxybutyrate (BHB) on colonic crypt cell proliferation and intestinal tumor growth.
- Utilizing cancer organoid assays and single-cell RNA sequencing on patient biopsies.
Main Results:
- Ketogenic diets demonstrated a significant tumor-inhibitory effect in CRC models.
- The ketone body beta-hydroxybutyrate (BHB) suppressed intestinal tumor growth and colonic cell proliferation.
- BHB acts via the Hcar2 receptor to induce the transcriptional regulator Hopx, inhibiting cell proliferation.
- Elevated BHB and active HOPX were associated with reduced intestinal epithelial proliferation in human CRC samples.
Conclusions:
- A BHB-triggered pathway involving Hcar2 and Hopx regulates intestinal tumorigenesis.
- Metabolic interventions with BHB may offer a complementary strategy for CRC prevention and treatment.
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