title: Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation.
abstract: Deubiquitinases (DUB) are increasingly linked to the regulation of fundamental processes in normal and cancer cells, including DNA replication and repair, programmed cell death, and oncogenes and tumor suppressor signaling. Here, evidence is presented that the deubiquitinase OTUD6B regulates protein synthesis in non-small cell lung cancer (NSCLC) cells, operating downstream from mTORC1. OTUD6B associates with the protein synthesis initiation complex and modifies components of the 48S preinitiation complex. The two main OTUD6B splicing isoforms seem to regulate protein synthesis in opposing fashions: the long OTUD6B-1 isoform is inhibitory, while the short OTUD6B-2 isoform stimulates protein synthesis. These properties affect NSCLC cell proliferation, because OTUD6B-1 represses DNA synthesis while OTUD6B-2 promotes it. Mutational analysis and downstream mediators suggest that the two OTUD6B isoforms modify different cellular targets. OTUD6B-2 influences the expression of cyclin D1 by promoting its translation while regulating (directly or indirectly) c-Myc protein stability. This phenomenon appears to have clinical relevance as NSCLC cells and human tumor specimens have a reduced OTUD6B-1/OTUD6B-2 mRNA ratio compared with normal samples. The global OTUD6B expression level does not change significantly between nonneoplastic and malignant tissues, suggesting that modifications of splicing factors during the process of transformation are responsible for this isoform switch.
  
  
  
  Because protein synthesis inhibition is a viable treatment strategy for NSCLC, these data indicate that OTUD6B isoform 2, being specifically linked to NSCLC growth, represents an attractive, novel therapeutic target and potential biomarker for early diagnosis of malignant NSCLC. Mol Cancer Res; 15(2); 117-27. ©2016 AACR.
authors.affiliation: Department of Pathology and Oncology Institute, Loyola University Chicago, Maywood, Illinois.
authors.forename: Anna
authors.initials: A
authors.lastname: Sobol
authors.affiliation: Department of Pathology and Oncology Institute, Loyola University Chicago, Maywood, Illinois.
authors.forename: Caroline
authors.initials: C
authors.lastname: Askonas
authors.affiliation: Department of Pathology and Oncology Institute, Loyola University Chicago, Maywood, Illinois.
authors.forename: Sara
authors.initials: S
authors.lastname: Alani
authors.affiliation: Department of Pathology and Oncology Institute, Loyola University Chicago, Maywood, Illinois.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Weber
authors.affiliation: Department of Pathology and Oncology Institute, Loyola University Chicago, Maywood, Illinois.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ananthanarayanan
authors.affiliation: Department of Pathology and Oncology Institute, Loyola University Chicago, Maywood, Illinois.
authors.forename: Clodia
authors.initials: C
authors.lastname: Osipo
authors.affiliation: Department of Pathology and Oncology Institute, Loyola University Chicago, Maywood, Illinois. mbocche@luc.edu.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bocchetta
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D000072017:Deubiquitinating Enzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D007527:Isoenzymes; D000072017:Deubiquitinating Enzymes