β-Hydroxybutyrate suppresses colorectal cancer

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.