EPLIN downregulation promotes epithelial–mesenchymal transition in prostate cancer cells and correlates with clinical lymph node metastasis

Abstract

Epithelial-mesenchymal transition (EMT) is a crucial mechanism for the acquisition of migratory and invasive capabilities by epithelial cancer cells. By conducting quantitative proteomics in experimental models of human prostate cancer (PCa) metastasis, we observed strikingly decreased expression of EPLIN (epithelial protein lost in neoplasm; or LIM domain and actin binding 1, LIMA-1) upon EMT. Biochemical and functional analyses demonstrated that EPLIN is a negative regulator of EMT and invasiveness in PCa cells. EPLIN depletion resulted in the disassembly of adherens junctions, structurally distinct actin remodeling, and activation of β-catenin signaling. Microarray expression analysis identified a subset of putative EPLIN target genes associated with EMT, invasion and metastasis. By immunohistochemistry EPLIN downregulation was also demonstrated in lymph node metastases of human solid tumors including PCa, breast cancer, colorectal cancer and squamous cell carcinoma of the head and neck. This study reveals a novel molecular mechanism for converting cancer cells into a highly invasive and malignant form, and has important implications in prognosing and treating metastasis at early stages.

Epidermal Growth Factor Promotes Protein Degradation of Epithelial Protein Lost in Neoplasm (EPLIN), a Putative Metastasis Suppressor, during Epithelial-mesenchymal Transition

“…Immunofluorescence and Confocal Imaging-Immunofluorescence was performed as described previously (17). Mouse anti-EPLIN antibody, rabbit anti-E-cadherin antibody, or rabbit anti-␤-catenin antibody were used (Table 1).…”

“…1.25-g human EPLIN-␤ reporter plasmids were transfected with 0.25-g pRL-TK (internal control) as described previously (17). Cells The specific primer pairs are described in Table 3.…”

“…EPLIN was initially thought to be a potential tumor suppressor that is preferentially expressed in human epithelia but frequently lost in cancerous cells (11,16). Recently, we reported a novel role of EPLIN in the regulation of EMT and invasiveness (17). EPLIN depletion in epithelial-like PCa cells promoted the disassembly of adherens junction, structurally distinct actin remodeling, and activation of ␤-catenin signaling.…”

Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

“…Importantly, a reduction of hCDC14A and eplin levels is frequently observed in colorectal carcinoma and is associated with poor prognosis in cancer patients (Fig. 5 I and J) (20,34,35). Collectively, we propose that the balance of eplin phosphorylation that is maintained by the antagonistic activities of ERK and hCDC14A toward conserved phosphorylation sites on eplin plays a key role in regulating actin dynamics to modulate cell migration and adhesion of both normal and transformed cells (Fig.…”

“…Downregulation of eplin frequently occurs in cancer tissues and contributes to the epithelia-to-mesenchymal transition (EMT) that enhances cancer cell metastasis and chemo-resistance of tumors (23,(33)(34)(35)(36)(37).…”