Abstract 185P
Background
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Aberrant activation of Wnt/β-catenin signaling pathway is a prominent driver of HCC. Somatic mutations in CTNNB1 (25-30%), are among the most frequent alterations observed in HCC, particularly in Non-Alcoholic Fatty Liver Disease (NAFLD)-associated HCC. This suggests that CTNNB1 mutations may confer an advantageous regulatory role for tumor growth under metabolic/fatty acid dysfunction.
Methods
To investigate the genome-wide occupancy of CTNNB1 encoded β-catenin protein, chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) was performed in CTNNB1mut and CTNNB1wt patient-derived HCC organoids and cell lines.
Results
Showed that a significant enrichment of β-catenin binding peaks was observed in mutant CTNNB1 compared to wild type, where transcription factor SP5 was discovered for the first time as a novel direct target of CTNNB1mut. Since β-catenin is a transcriptional coactivator, further motif analysis of ChIP-seq data for transcription factor revealed that β-catenin peaks are highly enriched at SP5 motif. This suggested a plausible β-catenin/SP5 regulatory feed-forward loop. In fact, β-catenin/SP5 colocalizing peaks were further found to be enriched in genes involved in the metabolic pathways, particularly the upregulation of ketone metabolism. Our validation work confirmed a novel mutant β-catenin/SP5 axis that mediates metabolic reprogramming through ketogenesis in HCC.
Conclusions
These findings provide insights into the molecular mechanisms underlying the role of CTNNB1 mutations in HCC, especially under NAFLD pathogenesis.
Legal entity responsible for the study
The author.
Funding
Hong Kong Research Grants Council Area of Excellence Scheme (Ref. AoE/M-401/20).
Disclosure
The author has declared no conflicts of interest.
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