Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition

Abstract

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM's role in EMT may reveal additional therapeutic opportunities.

Keywords: cancer stem cells (CSCs); circulating tumor cells (CTCs); epithelial cancers; epithelial cell adhesion molecule (EpCAM); epithelial-to-mesenchymal transition (EMT); metastasis.

Figure 1

EpCAM has six domains. The protein consists of 314 amino acids. The signal peptide (SP) is typically cleaved, but is shown here. This is followed by the N-terminal domain (ND), the type-1 thyroglobulin domain (TY-1), and the carboxyl-terminal domain (CD). EpCAM has a single pass transmembrane domain (TM) and an intracellular domain (EpICD).

Figure 2

The regulation of EpCAM during EMT occurs through a double-negative feedback loop. In epithelial cells (left panel), EpCAM forms homophilic adhesions and promotes epithelial homeostasis. EpCAM can also inhibit ERK signaling (a potent mediator of EMT) and its gene targets, including SNAI2, EGR1, FOS, JUN, ATF3, and others. In mesenchymal cells (right panel), ERK pathway signaling silences EpCAM expression. ERK2 binds the EpCAM promoter at an ERK2-binding consensus sequence and directly inhibits EpCAM gene expression. ERK2 also induces EMT transcription factors, including SNAI2, that in turn also inhibit EpCAM transcription.

Figure 3

Regulated intramembrane proteolysis of EpCAM modulates EMT. EpEX and EGF simulate RIP, which is mediated by TACE and PSEN2 enzymatic cleavage. This occurs, in part, through ERK signaling. Upon EpCAM cleavage, EpICD is transported into the nucleus. EpICD binds FHL2, LEF1, and β-catenin to form a nuclear DNA binding complex that promotes transcription of target genes and in turn causes tumor growth and EMT. EpCAM has also been shown to be a negative regulator of E-cadherin. This may free β-catenin for downstream signaling with EpICD.