title: Chromosome instability modulated by BMI1-AURKA signaling drives progression in head and neck cancer.
abstract: Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1-AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chou
authors.forename: Neng-Kai
authors.initials: NK
authors.lastname: Yang
authors.forename: Ting-Yun
authors.initials: TY
authors.lastname: Liu
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.forename: Dennis Shin-Shian
authors.initials: DS
authors.lastname: Hsu
authors.forename: Ya-Wei
authors.initials: YW
authors.lastname: Chen
authors.forename: Yann-Jang
authors.initials: YJ
authors.lastname: Chen
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
mesh_terms: D064096:Aurora Kinase A; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D018450:Disease Progression; D004789:Enzyme Activation; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; D051176:beta Catenin; D063150:Polycomb Repressive Complex 1; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt