title: OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination.
abstract: Activation of the RAS oncogenic pathway, frequently ensuing from mutations in RAS genes, is a common event in human cancer. Recent reports demonstrate that reversible ubiquitination of RAS GTPases dramatically affects their activity, suggesting that enzymes involved in regulating RAS ubiquitination may contribute to malignant transformation. Here, we identified the de-ubiquitinase OTUB1 as a negative regulator of RAS mono- and di-ubiquitination. OTUB1 inhibits RAS ubiquitination independently of its catalytic activity resulting in sequestration of RAS on the plasma membrane. OTUB1 promotes RAS activation and tumorigenesis in wild-type RAS cells. An increase of OTUB1 expression is commonly observed in non-small-cell lung carcinomas harboring wild-type KRAS and is associated with increased levels of ERK1/2 phosphorylation, high Ki67 score, and poorer patient survival. Our results strongly indicate that dysregulation of RAS ubiquitination represents an alternative mechanism of RAS activation during lung cancer development.
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Baietti
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Michal
authors.initials: M
authors.lastname: Simicek
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Layka
authors.initials: L
authors.lastname: Abbasi Asbagh
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: Department of Medical Protein Research, VIB, Leuven, Belgium Department of Biochemistry, Gent University, Gent, Belgium.
authors.forename: Sam
authors.initials: S
authors.lastname: Lievens
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Crowther
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Steklov
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium Institute of Carcinogenesis, Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Vasily N
authors.initials: VN
authors.lastname: Aushev
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Martínez García
authors.affiliation: Department of Medical Protein Research, VIB, Leuven, Belgium Department of Biochemistry, Gent University, Gent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, KU Leuven, Leuven, Belgium anna.sablina@cme.vib-kuleuven.be.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Sablina
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D008819:Mice, Nude; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000072017:Deubiquitinating Enzymes; C538826:OTUB1 protein, human; D003546:Cysteine Endopeptidases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: RAS; lung cancer; reversible ubiquitination