51474

LIMA1

LIM domain and actin binding 1;LIMA1;LIM domain and actin binding 1

1110021C24Rik|LIM domain and actin-binding protein 1|epithelial protein lost in neoplasm beta|sterol regulatory element binding protein 3

12q13

protein-coding

Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.

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 beta-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 prognosis and treating metastasis at early stages.

Aberrant expression of EGF receptors has been associated with hormone-refractory and metastatic prostate cancer (PCa). However, the molecular mechanism for EGF signaling in promoting PCa metastasis remains elusive. Using experimental models of PCa metastasis, we demonstrated that EGF could induce robust epithelial-mesenchymal transition (EMT) and increase invasiveness. Interestingly, EGF was found to be capable of promoting protein turnover of epithelial protein lost in neoplasm (EPLIN), a putative suppressor of EMT and tumor metastasis. Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. This study elucidated a novel molecular mechanism for EGF regulation of EMT and invasiveness in PCa cells, indicating that blockade of EGF signaling could be beneficial in preventing and retarding PCa metastasis at early stages.