Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis.
Through genome-wide gene expression analysis of lung carcinomas, we detected in the great majority of lung cancer samples cotransactivation of cell division cycle associated 8 (CDCA8) and aurora kinase B (AURKB), which were considered to be components of the vertebrate chromosomal passenger complex. Immunohistochemical analysis of lung cancer tissue microarrays showed that overexpression of CDCA8 and AURKB was significantly associated with poor prognosis of lung cancer patients. AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells. Suppression of CDCA8 expression with small interfering RNA against CDCA8 significantly suppressed the growth of lung cancer cells. In addition, functional inhibition of interaction between CDCA8 and AURKB by a cell-permeable peptide corresponding to 20-amino acid sequence of a part of CDCA8 (11R-CDCA8(261-280)), which included two phosphorylation sites by AURKB, significantly reduced phosphorylation of CDCA8 and resulted in growth suppression of lung cancer cells. Our data imply that selective suppression of the CDCA8-AURKB pathway could be a promising therapeutic strategy for treatment of lung cancer patients.
Hayama
Satoshi
S
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Daigo
Yataro
Y
Yamabuki
Takumi
T
Hirata
Daizaburo
D
Kato
Tatsuya
T
Miyamoto
Masaki
M
Ito
Tomoo
T
Tsuchiya
Eiju
E
Kondo
Satoshi
S
Nakamura
Yusuke
Y
D000595:Amino Acid Sequence; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
C490157:CDCA8 protein, human; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D010455:Peptides; D034741:RNA, Small Interfering; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases