title: Evidence for the ubiquitin protease UBP43 as an antineoplastic target.
abstract: New pharmacologic targets are needed for lung cancer. One candidate pathway to target is composed of the E1-like ubiquitin-activating enzyme (UBE1L) that associates with interferon-stimulated gene 15 (ISG15), which complexes with and destabilizes cyclin D1. Ubiquitin protease 43 (UBP43/USP18) removes ISG15 from conjugated proteins. This study reports that gain of UBP43 stabilized cyclin D1, but not other D-type cyclins or cyclin E. This depended on UBP43 enzymatic activity; an enzymatically inactive UBP43 did not affect cyclin D1 stability. As expected, small interfering RNAs that reduced UBP43 expression also decreased cyclin D1 levels and increased apoptosis in a panel of lung cancer cell lines. Forced cyclin D1 expression rescued UBP43 apoptotic effects, which highlighted the importance of cyclin D1 in conferring this. Short hairpin RNA-mediated reduction of UBP43 significantly increased apoptosis and reduced murine lung cancer growth in vitro and in vivo after transplantation of these cells into syngeneic mice. These cells also exhibited increased response to all-trans-retinoic acid, interferon, or cisplatin treatments. Notably, gain of UBP43 expression antagonized these effects. Normal-malignant human lung tissue arrays were examined independently for UBP43, cyclin D1, and cyclin E immunohistochemical expression. UBP43 was significantly (P < 0.01) increased in the malignant versus normal lung. A direct relationship was found between UBP43 and cyclin D1 (but not cyclin E) expression. Differential UBP43 expression was independently detected in a normal-malignant tissue array with diverse human cancers. Taken together, these findings uncovered UBP43 as a previously unrecognized antineoplastic target.
authors: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors: Yongli
authors: Y
authors: Guo
authors: Fadzai
authors: F
authors: Chinyengetere
authors: Andrey V
authors: AV
authors: Dolinko
authors: Alexandra
authors: A
authors: Lopez-Aguiar
authors: Yun
authors: Y
authors: Lu
authors: Fabrizio
authors: F
authors: Galimberti
authors: Tian
authors: T
authors: Ma
authors: Qing
authors: Q
authors: Feng
authors: David
authors: D
authors: Sekula
authors: Sarah J
authors: SJ
authors: Freemantle
authors: Angeline S
authors: AS
authors: Andrew
authors: Vincent
authors: V
authors: Memoli
authors: Ethan
authors: E
authors: Dmitrovsky
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D058990:Molecular Targeted Therapy; D016297:Mutagenesis, Site-Directed; D009368:Neoplasm Transplantation; D055550:Protein Stability; D034622:RNA Interference; D046888:Tissue Array Analysis; D014212:Tretinoin / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056741:Cyclin D; D019927:Cyclin E; D016207:Cytokines; D014452:Ubiquitins; D014212:Tretinoin; C074034:ISG15 protein, human; D007372:Interferons; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase; D002945:Cisplatin