title: FBXW7 mediates chemotherapeutic sensitivity and prognosis in NSCLCs.
abstract: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I-specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7.
  
  
  CONCLUSIONS
  FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg.
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showamachi, Maebashi 371-8511 Japan. bori45@gunma-u.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokobori
authors.forename: Yozo
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Akira
authors.initials: A
authors.lastname: Mogi
authors.forename: Hideki
authors.initials: H
authors.lastname: Endoh
authors.forename: Bolag
authors.initials: B
authors.lastname: Altan
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kosaka
authors.forename: Ei
authors.initials: E
authors.lastname: Yamaki
authors.forename: Toshiki
authors.initials: T
authors.lastname: Yajima
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomizawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Azuma
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Onozato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Shigebumi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044783:F-Box Proteins / Q000096:biosynthesis / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D017239:Paclitaxel / Q000494:pharmacology; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D012907:Smoking / Q000009:adverse effects; D013534:Survival; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D056572:Histone Deacetylase Inhibitors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000075223:Poly-ADP-Ribose Binding Proteins; D011725:Pyridines; D034741:RNA, Small Interfering; C118739:entinostat; D044767:Ubiquitin-Protein Ligases; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; D017239:Paclitaxel