Abstract
Ubiquilin1 (UBQLN1) is a ubiquitin-like domain and a ubiquitin-associated domain containing protein that has been reported to be involved in shuttling proteins to the proteasome, especially during endoplasmic reticulum-associated protein degradation (ERAD). Thus, UBQLN1 function has been shown to be critical for combating a number of neurological disorders caused by protein aggregation, such as Amyotrophic lateral sclerosis (ALS), Alzheimer's disease and Huntington's disease. A role for UBQLN1 in regulating processes involved in tumorigenesis has not been demonstrated. Herein, we show that loss of UBQLN1 causes increased cell migration and invasion, actin cytoskeleton reorganization and induction of epithelial mesenchymal transition (EMT). Loss of UBQLN1 results in a significant decrease in the expression of epithelial markers including E-cadherin and claudin1, whereas expression of mesenchymal markers including Vimentin, Snail and ZEB1 are significantly elevated. Interestingly, we found that ZEB1 is required for induction of mesenchymal-like properties following loss of UBQLN1 and ZEB1 is capable of repressing expression of UBQLN1, suggesting a physiological, reciprocal regulation of EMT by UBQLN1 and ZEB1. Furthermore, we observed that loss of UBQLN1 sensitizes lung cancer cells to treatment with cytotoxic drugs. These observations have potential clinical relevance because the UBQLN1 gene is lost and under-expressed in a large percentage of human cancer cell lines and primary human lung cancer samples. Taken together, our results suggest for the first time a role of UBQLN1 in the regulation of EMT and a potential role in cancer biology and in predictive cancer therapeutics.
Citation Format: Parag P. Shah, William W. Lockwood, Kumar Saurabh, Zimple Kurlawala, Sabine Waigel, Wolfgang Zacharias, Levi J. Beverly. Ubiquilin1 represses migration and epithelial to mesenchymal transition of human non-small cell lung cancer cells. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A05.