Investigating the role of ABHD11 in colorectal cancer

Abstract

Metabolic reprogramming is one of the hallmarks of colorectal cancer (CRC) development. One of the metabolic pathways most commonly dysregulated in CRC is the tricarboxylic acid (TCA) cycle, which provides intermediates involved in biosynthesis, as well as signalling, such as alpha-ketoglutarate (α-KG). This metabolite has been shown to regulate gene expression via enzymes called α-KG-dependent dioxygenases (α-KGDDs) that are responsible for DNA and histone demethylation. Activity of these enzymes induces cell differentiation, and downregulates Wnt signalling, while impaired function of α-KGDDs promotes Wnt signalling and stemness. Therefore, α-KG is likely important in CRC, and it is crucial to investigate its regulatory mechanisms, such as the conversion of α-KG into succinyl-CoA, the next metabolite in the TCA cycle, by the enzyme α-KG dehydrogenase complex (α-KGDHC). The activity of α-KGDHC is supported by a protein called αβ-hydrolase domain-containing protein 11 (ABHD11), while loss of ABHD11 has been found to downregulate α-KGDHC activity. Hence, modulation of ABHD11 activity may provide a novel way to regulate the level of cellular α-KG, and therefore cell physiology. This project investigated the effect of ABHD11 inhibition on the viability and growth of organoids modelling different stages of CRC development. The expression of stem and differentiation markers upon ABHD11 inhibition was also measured. The results revealed that ABHD11 is important for viability and growth of organoids. Additionally, ABHD11 inhibition may modulate stemness and differentiation of the organoids, although further experiments are necessary for conclusive results. The preliminary results obtained within this project, as well as optimization of organoid assays, provide a foundation for future work focusing on further uncovering the role of ABHD11 in CRC. This would allow for determining whether increasing the level of α-KG via ABHD11 inhibition would have therapeutic benefits in CRC, by promoting differentiation and reducing proliferation.

Date of Award	1 Oct 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Emma E Vincent (Supervisor) & Gareth Jones (Supervisor)