APC loss promotes endometrial cancer progression by upregulating FGF12 expression: An integrated multi-omics analysis

Endometrial cancer (EC) is one of the most common gynecological cancers worldwide. High-order chromatin structure plays a critical role in regulating gene expression. Our previous study identified frequent mutations in the chromatin remodeling-related gene adenomatous polyposis coli ( APC ) in EC. Here, we investigated the role of APC in chromatin remodeling and EC progression.

The efforts of APC against EC cells in vitro and in vivo were characterized by g ene expression and overall survival analysis with The Cancer Genome Atlas (TCGA) database, Western blotting, RNA isolation and quantitative real-time polymerase chain reaction (RT-PCR), the integrated multiomics analysis, lentivirus transfection, nude mice tumorigenesis experiment, and immunohistochemistry.

APC expression was reduced in EC tissues, and APC -knockdown KLE cells exhibited enhanced cell migration. Integrated multi-omics analyses, including RNA sequencing (RNA-seq), assay for transposase-accessible chromatin by high-throughput sequencing (ATAC-seq), and high-through chromosome conformation capture (Hi-C), compared control and APC -knockdown KLE cells. These analyses identified fibroblast growth factor 12 ( FGF12 ) as a differentially expressed gene (DEG) localized to switched chromatin compartments, cell-specific boundaries, and loops, with elevated expression in APC -knockdown cells. High FGF12 expression correlated with poor prognosis in EC patients. Knockdown of FGF12 in APC -deficient KLE cells reversed the enhanced migratory phenotype.

Loss of APC promotes EC cell migration and reprograms chromatin architecture to upregulate FGF12 , activating tumorigenesis-related protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways and driving EC progression. Elevated FGF12 levels are associated with poor prognosis, highlighting its potential as a therapeutic target for EC patients with low APC expression.