Attenuated APC contributes to FGF12 expression and EC progression with an integrated multi-omics analysis

Abstract

AbstractBackgroundEndometrial cancer (EC) is one of the most common gynecological cancer worldwide. The high-order chromatin structure plays an important role in gene expression regulation. In our previous research, the chromatin remodeling-related gene APC (adenomatous polyposis coli gene) is frequently mutated in endometrial cancer. In this study, we aimed to figure out the role of the APC gene in the chromatin remodeling of endometrial cancer and cancer progression.ResultsThe level of APC expression decreased in EC and cell migration assays revealed that APC know-down KLE cells showed increased cell migration ability. An integrated multi-omics analysis, including RNA-sequencing (RNA-seq), assay for transposable accessible chromatin by high-throughput sequencing (ATAC-seq) and Hi-C, between the control cell and APC and knockdown KLE cell was performed and revealed that FGF12 was identified as a differentially expressed gene (DEG) in the switched compartments, cell-specific boundaries, and loops by comparing hierarchical structures and highly expressed in APC knockdown KLE cells. Moreover, high expression of FGF12 indicated a poor prognosis.ConclusionsAPC expression decreased in EC tissues and loss of APC in EC promotes cell migration. Moreover, loss of APC gene expression may reprogram the chromatin architecture to increase FGF12 gene expression, activate tumorigenesis-rated AKT and MAPK (Erk1/2) signaling, and promote endometrial cancer progression. In addition, a high level of FGF12 expression indicated a poor prognosis in EC patients, which provides a novel therapeutic target for EC with low expression level APC.