HOXC9 enhances cholesterol metabolism and malignancy in pancreatic ductal adenocarcinoma through ITGA10/FAK/PI3K/CREB-dependent HMGCR activation

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Dysregulated cholesterol metabolism contributes to tumor progression, but its regulatory mechanisms in PDAC are unclear. This study explored the role and mechanism of homeobox C9 (HOXC9) in cholesterol regulation and PDAC development. METHODS: HOXC9 was identified by bioinformatics as a key cholesterol metabolism gene in PDAC. Its expression was validated via qRT-PCR, Western blot, and immunohistochemistry, while cholesterol were measured using microassay and Filipin III staining. In vitro assays and subcutaneous tumor models in nude mice were used to assess its functional roles. RNA-seq, ChIP-qPCR, and dual-luciferase reporter assays explored molecular mechanisms. RESULTS: HOXC9 was identified as a key cholesterol metabolism-related transcription factor in PDAC. High-throughput data analysis based on TCGA databases further revealed that HOXC9 was highly expressed in PDAC tissues and associated with dismal prognosis. Clinically, HOXC9 upregulation correlates positively with tumor cholesterol, advanced stage, and reduced survival. Functionally, HOXC9 promotes PDAC cell proliferation, migration, and invasion in a cholesterol-dependent manner. In vivo, HOXC9 knockdown suppressed tumor growth and intratumoral cholesterol in nude mice, an effect reversible by high-cholesterol diet. Mechanistically, transcriptome sequencing highlighted the PI3K-Akt pathway as a key downstream target. HOXC9 transcriptionally activates ITGA10, which upregulates HMGCR via the FAK/PI3K/CREB, thereby driving cholesterol metabolism and tumor progression. CONCLUSIONS: HOXC9 may be a key transcriptional regulator of cholesterol metabolism in PDAC, promoting malignant progression by activating the ITGA10/FAK/PI3K/CREB to regulate HMGCR-mediated cholesterol synthesis. The essential role of the HOXC9-ITGA10-cholesterol axis in PDAC progression offers a novel potential target for therapy.