CBX3 Downregulates HLTF to Activate PI3K/AKT Signaling Promoting Cholangiocarcinoma

Abstract Cholangiocarcinoma (CCA) is an aggressive cancer with poor response to chemotherapy or radiation, necessitating novel therapeutic approaches. Epigenetic regulation, which is reversible, plays a significant role in cancer progression. CBX3 (HP1γ), a key heterochromatin protein, regulates gene expression by interacting with histone H3 lysine 9 trimethyl (H3K9me3) markers. While CBX3 is linked to tumor progression in various cancers, its role in CCA remains unclear. This study reveals that CBX3 and H3K9me3 enrich the HLTF promoter, a gene involved in chromatin remodeling and DNA repair. HLTF is often inactivated by hypermethylation in other cancers, suggesting tumor‐suppressive properties. Depleting CBX3 in CCA cells elevates HLTF expression, reducing proliferation, while HLTF silencing reverses this effect. Furthermore, HLTF overexpression inhibits PI3K‐AKT signaling activated by CBX3. These findings suggest CBX3 promotes CCA progression by suppressing HLTF expression.