title: Ubiquilin1 represses migration and epithelial-to-mesenchymal transition of human non-small cell lung cancer cells.
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. 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, 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-to-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. Further, we find evidence for a role for UBQLN2 in also regulating EMT and cell migration. These observations have potential clinical relevance because the UBQLN1 gene is lost and underexpressed in a large percentage of human cancer cell lines, and primary human lung cancer samples and recurrent mutations in all five UBQLN family members have been identified in human lung cancers. Taken together, our results suggest for the first time a role for UBQLN family members in cancer biology.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: Cancer Biology and Genetics Section, Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: W W
authors.initials: WW
authors.lastname: Lockwood
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Saurabh
authors.affiliation: 1] James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Kurlawala
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Shannon
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Waigel
authors.affiliation: 1] James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA [3] Division of Hematology and Oncology, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zacharias
authors.affiliation: 1] James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA [3] Division of Hematology and Oncology, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Beverly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000502:physiology; D000071183:Autophagy-Related Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D059865:Endoplasmic Reticulum Stress; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D014157:Transcription Factors / Q000502:physiology; D000074405:Valosin Containing Protein; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; C107792:UBQLN1 protein, human; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein
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