title: UBE1L causes lung cancer growth suppression by targeting cyclin D1.
abstract: UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Remsen 7650, Hanover, NH 03755, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Feng
authors.forename: David
authors.initials: D
authors.lastname: Sekula
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guo
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.forename: Candice C
authors.initials: CC
authors.lastname: Black
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Galimberti
authors.forename: Sumit J
authors.initials: SJ
authors.lastname: Shah
authors.forename: Lorenzo F
authors.initials: LF
authors.lastname: Sempere
authors.forename: Vincent
authors.initials: V
authors.lastname: Memoli
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.forename: Bret A
authors.initials: BA
authors.lastname: Hassel
authors.forename: Konstantin
authors.initials: K
authors.lastname: Dragnev
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000077610:Bexarotene; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism*; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D044764:Ubiquitin-Activating Enzymes / Q000737:chemistry / Q000502:physiology*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D016207:Cytokines; D019394:Ki-67 Antigen; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014452:Ubiquitins; D019938:Cyclin D1; C074034:ISG15 protein, human; D003513:Cycloheximide; D000077610:Bexarotene; C534879:UBA7 protein, human; D044764:Ubiquitin-Activating Enzymes