Safely Targeting Cancer, the Wound That Never Heals, Utilizing CBP/Beta-Catenin Antagonists

Area of Science:

• Cellular Biology
• Epigenetics
• Cancer Stem Cell Biology

Background:

• Stem cells (SSC and CSC) exhibit quiescent and activated states, relying on distinct metabolic pathways (FAO and glycolysis, respectively).
• Quiescence is vital for SSC genomic integrity and a key factor in CSC therapy resistance, latency, and relapse.
• CREBBP (CBP) and EP300 (p300) are homologous Kat3 coactivators with critical, non-redundant roles in regulating stem cell states and metabolism via H3K27 acetylation.

Purpose of the Study:

• To review the distinct regulatory roles of CBP and p300 in stem cell biology.
• To explore the potential of targeting the CBP/β-catenin interaction to eliminate quiescent CSC.

Main Methods:

• Review of existing literature on stem cell states, metabolism, and epigenetic regulation.
• Analysis of the roles of CBP and p300 in controlling stem cell quiescence and activation.
• Discussion of small molecule antagonists targeting the CBP/β-catenin interaction.

Main Results:

• CBP and p300 play non-redundant roles in controlling stem cell quiescence versus activation through H3K27 acetylation at enhancers.
• These coactivators influence stem cell metabolic requirements, linking quiescence to FAO and activation to glycolysis.
• Targeting the CBP/β-catenin interaction shows promise in correcting lineage infidelity and eliminating quiescent CSC.

Conclusions:

• CBP and p300 are crucial regulators of stem cell state and metabolism.
• Targeting the CBP/β-catenin interaction represents a potential therapeutic strategy against quiescent CSC, offering a way to overcome therapy resistance and relapse.