ACLY alternative splicing correlates with cancer phenotypes

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• ATP-citrate lyase (ACLY) is crucial for linking carbohydrate and lipid metabolism, supplying acetyl-CoA for cellular processes.
• ACLY exists as two splice isoforms: a full-length 'long' form and a 'short' form lacking exon 14.
• Altered splicing of ACLY exon 14 is observed in various cancers, correlating with poorer survival, prompting investigation into isoform-specific functions.

Purpose of the Study:

• To investigate potential biochemical and functional differences between ACLY long and short isoforms.
• To explore the impact of ACLY exon 14 splicing on cellular metabolism, stability, and cancer progression.
• To identify regulatory mechanisms of ACLY splicing and its correlation with tumor immune microenvironments.

Main Methods:

• In vitro assays to assess enzymatic activity and stability of ACLY isoforms and phosphomutants.
• Re-expression studies in Acly knockout cells to evaluate isoform function in fatty acid synthesis and histone acetylation.
• Analysis of transcriptomic data, mouse models of cancer, and correlation studies with splicing regulatory factors.

Main Results:

• No discernible differences in enzymatic activity or stability were found between ACLY isoforms or phosphomutants in vitro.
• Both isoforms effectively rescued ACLY functions, including fatty acid synthesis and histone acetylation, in knockout cells.
• Deletion of exon 14 in mice did not affect development or metabolic physiology, nor did it alter tumor burden in a cancer model.
• ACLY splicing is regulated by ESRP1, and both ESRP1 expression and ACLY splicing patterns correlate with tumor immune signatures.

Conclusions:

• Despite altered splicing patterns in cancer, no functional differences were identified between ACLY isoforms in vitro or in vivo.
• The splicing of ACLY exon 14 is regulated by ESRP1 and is associated with specific immune signatures in tumors.
• The functional significance of ACLY isoform variation in cancer remains elusive and warrants further research.