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A Nuclear Isoform of Hydroxyacyl-CoA Dehydrogenase Inhibits Tumor Progression In Colorectal Cancer

GSE253660 Homo sapiens Expression profiling by high throughput sequencing; Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2025/12/09 Platform GPL24676
Summary
Alternate translation initiation expands protein diversity which is adopted by cancers for progression. However, the majority of these alternative initiation events in cancers remain largely undefined. In this study, we demonstrate that the human hydroxyacyl-CoA dehydrogenase (HADH) gene, catalyzing the third step of the mitochondrial β-oxidation cascade, has two alternative translation start codons. The translation from the downstream start codon produces a short isoform (HADH-S) primarily localized in the nucleus. HADH-S is downregulated in colorectal cancer. Overexpression of HADH-S inhibits colorectal tumorigenesis in vitro and in vivo. Mechanistically, HADH-S antagonizes protein arginine methyltransferase 5 (PRMT5)-mediated histone arginine methylation, thereby facilitating gene transcription. Notably, HADH promotes the transcription of the Wnt suppressor AXIN2. These findings collectively identify a novel nuclear isoform of HADH that exerts inhibitory effects on colorectal tumorigenesis.
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Also filed as BioProject PRJNA1066725 and SRA study SRP484701. Searching any of these in the dataset finder brings you back here.

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