TY - JOUR
T1 - Chromosome instability modulated by BMI1-AURKA signaling drives progression in head and neck cancer
AU - Chou, Chun Hung
AU - Yang, Neng Kai
AU - Liu, Ting Yun
AU - Tai, Shyh Kuan
AU - Hsu, Dennis Shin Shian
AU - Chen, Ya Wei
AU - Chen, Yann Jang
AU - Chang, Cheng Chi
AU - Tzeng, Cheng Hwai
AU - Yang, Muh Hwa
PY - 2013/1/15
Y1 - 2013/1/15
N2 - 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 chromatinmodifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stemlike 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.
AB - 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 chromatinmodifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stemlike 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.
UR - http://www.scopus.com/inward/record.url?scp=84872566499&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-2397
DO - 10.1158/0008-5472.CAN-12-2397
M3 - Article
AN - SCOPUS:84872566499
SN - 0008-5472
VL - 73
SP - 953
EP - 966
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -
