title: Small interfering RNA-induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors.
abstract: Alterations in the function of cell cycle checkpoints are frequently detected in oral squamous cell carcinomas (OSCCs), and are often associated with the sensitivity of the cancer cells to chemotherapeutic drugs. Recently, a mitotic checkpoint gene, Chfr, was shown to be inactivated by promoter methylation and point mutations in various human tumors. Here we show that the absence of its product, CHFR, is associated with mitotic checkpoint dysfunction, and that cancer cells lacking CHFR are sensitive to microtubule inhibitors. Checkpoint impairment appears to be caused by a prophase defect in this case, as OSCC cells lacking CHFR showed phosphorylation of histone H3 on Ser10 and translocation of cyclin B1 to the nucleus. When CHFR-deficient OSCC cells were treated with a microtubule inhibitor (docetaxel or paclitaxel), significant numbers of apoptotic cells were observed. Moreover, disruption of CHFR using small interfering RNA (siRNA) impaired the mitotic checkpoint, thereby reducing the ability of OSCC cells to arrest at G2/M phase and making them more sensitive to microtubule inhibitors. Our results suggest that CHFR could be a useful molecular target for chemotherapy.
authors.affiliation: Department of Molecular Biology, Cancer Research Institute, Department of Oral Surgery, Sapporo Medical University, Sapporo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogi
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mita
authors.forename: Ayumi
authors.initials: A
authors.lastname: Satoh
authors.forename: Lisa
authors.initials: L
authors.lastname: Kashima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kimishige
authors.initials: K
authors.lastname: Akino
authors.forename: Noriko
authors.initials: N
authors.lastname: Nishikawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Noguchi
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Hiratsuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D017239:Paclitaxel