Silencing ESRP1 expression promotes caspase-independent cell death via nuclear translocation of AIF in colon cancer cells

Abstract

Epithelial splicing regulatory protein 1 (ESRP1) is overexpressed in the majority of cancer types, while downregulated in a few cancers, thus it has emerged as a tumorigenic or a tumor suppressor depending on disease context and cell type. Moreover, the underlying molecular mechanism of ESRP1 is poorly understood in cancer progression. Here, we initially analyzed Clinical Proteomic Tumor Analysis Consortium (CPTAC), colon tissue microarray, and colon cancer cells to evaluate the ESRP1 expression levels in colorectal cancer subtypes. The association between the expression of ESRP1 and cell death signaling pathways was evaluated in colon cancer cells. Furthermore, silencing ESRP1 was performed to detect the relation between ESRP1 and apoptosis-inducing factor (AIF). Subsequently, translocation of AIF and apoptosis were analyzed by immunofluorescence assay and FACS, respectively. ESRP1 is found to be expressed at high levels in the early stage, and gradually decreases with the increasing colorectal cancer stage, wherein epithelial cell to mesenchymal cell transition (EMT) occurs during cancer progression. Moreover, ESRP1 silencing in HCT116 colorectal cancer cells reveals the translocation of the caspase-independent cell death marker AIF to the nucleus, thereby enhancing the DNA damage response, which inevitably induces cancer cell death. Our results demonstrate that silencing ESRP1 in colorectal cancer cells promotes HCT116 cell death by inducing caspase-independent cell death via regulation of CD44 alternative splicing. Collectively, our findings provide an insight into ESRP1 as a therapeutic target in colon cancer.