GCN5-mediated acetylation of YY1 enhances ZDHHC9-dependent palmitoylation of RNF14 and promotes colorectal cancer progression

Colorectal cancer (CRC) is among the most prevalent cancers worldwide, and dysregulated lipid metabolism is a hallmark of CRC. In particular, alterations in lipid metabolism in the circulating and non-circulating tumor tissues contribute to CRC development and progression. However, the precise molecular mechanisms that link lipid metabolic reprogramming to CRC pathogenesis remain unclear. CRC cell lines and a mouse xenograft model were used to investigate the roles of RING finger protein 14 (RNF14) palmitoylation, zinc finger DHHC-type palmitoyltransferase 9 (ZDHHC9), general control of amino acid synthesis 5-like 2 (GCN5), and Yin Yang 1 (YY1) in regulating lipid metabolism. Adenoviral transduction was used to introduce wild-type and palmitoylation-deficient RNF14 constructs. Protein expression, post-translational modifications, and protein–protein interactions were analyzed using western blotting, immunoprecipitation, and immunofluorescence. RNF14 palmitoylation levels were measured using an acyl resin-assisted capture assay. Cell viability was examined using the Cell Counting Kit-8 assay. Palmitoylation of RNF14 at cysteine 407 stabilized the protein by preventing ubiquitin-mediated degradation, thereby enhancing lipid metabolism and promoting tumor growth. This palmitoylation reaction was catalyzed by ZDHHC9. Silencing ZDHHC9 disrupted RNF14 palmitoylation, impaired lipid metabolism, and strongly suppressed tumor progression. Furthermore, the GCN5-mediated acetylation of YY1 activated ZDHHC9 expression, thereby forming a regulatory axis that enhanced RNF14 palmitoylation and lipid metabolic reprogramming. This study reveals a novel palmitoylation-dependent mechanism that regulates lipid metabolism in CRC. Accordingly, targeting the GCN5–YY1–ZDHHC9–RNF14 axis may be a promising therapeutic strategy against CRC.