EPLIN-β is a novel substrate of ornithine decarboxylase antizyme 1 and mediates cellular migration

Polyamines promote cellular proliferation. Their levels are controlled by ornithine decarboxylase antizyme 1 (Az(1), encoded by OAZ1), through the proteasome-mediated, ubiquitin-independent degradation of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis. Az(1)-mediated degradation of other substrates such as cyclin D1 (CCND1), DNp73 (TP73) or Mps1 regulates cell growth and centrosome amplification, and the currently known six Az(1) substrates are all linked with tumorigenesis. To understand whether Az(1)-mediated protein degradation might play a role in regulating other cellular processes associated with tumorigenesis, we employed quantitative proteomics to identify novel Az(1) substrates. Here, we describe the identification of LIM domain and actin-binding protein 1 (LIMA1), also known as epithelial protein lost in neoplasm (EPLIN), as a new Az(1) target. Interestingly, between the two EPLIN isoforms (α and β), only EPLIN-β is a substrate of Az(1). The interaction between EPLIN-β and Az(1) appears to be indirect, and EPLIN-β is degraded by Az(1) in a ubiquitination-independent manner. Az(1) absence leads to elevated EPLIN-β levels, causing enhanced cellular migration. Consistently, higher LIMA1 levels correlate with poorer overall survival of colorectal cancer patients. Overall, this study identifies EPLIN-β as a novel Az(1) substrate regulating cellular migration.