Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Cancer cells exhibit altered metabolism, with the tricarboxylic acid (TCA) cycle being central.
• Alternative splicing (AS) influences cancer metabolism, but its role in TCA cycle enzyme regulation is not fully understood.

Purpose of the Study:

• To investigate the impact of alternative splicing on citrate synthase (CS) in colorectal cancer.
• To characterize a novel CS splicing isoform and its role in cancer metabolism and progression.

Main Methods:

• Identification and characterization of a novel CS splicing isoform (CS-ΔEx4) in colorectal cancer.
• Analysis of CS-ΔEx4's effect on CS activity, mitochondrial respiration, and metabolic flux.
• Investigation of the link between CS-ΔEx4, 2-hydroxyglutarate levels, and epigenetic alterations.

Main Results:

• A novel CS isoform, CS-ΔEx4, is highly expressed in colorectal cancer.
• CS-ΔEx4 enhances CS activity, increasing mitochondrial respiration and driving glycolytic carbon into the TCA cycle.
• This leads to elevated 2-hydroxyglutarate, promoting epigenetic changes that support tumor progression.

Conclusions:

• Alternative splicing of citrate synthase directly contributes to cancer hallmarks.
• CS-ΔEx4 promotes metabolic reprogramming and epigenetic alterations supporting colorectal cancer growth and metastasis.
• Targeting CS-ΔEx4 presents a potential therapeutic strategy for colorectal cancer.