Chromosome instability modulated by BMI1-AURKA signaling drives progression in head and neck cancer

Chun Hung Chou, Neng Kai Yang, Ting Yun Liu, Shyh Kuan Tai, Dennis Shin Shian Hsu, Ya Wei Chen, Yann Jang Chen, Cheng Chi Chang, Cheng Hwai Tzeng, Muh Hwa Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)953-966
Number of pages14
JournalCancer Research
Volume73
Issue number2
DOIs
StatePublished - 15 Jan 2013

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