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 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 b-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let7i 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. Cancer Res; 73(2); 953-66. Ó2012 AACR.

Mechanisms of genome instability induced by RNA-processing defects

“…Recent examples have linked altered chromatin or transcription specifically to expression of genome stability factors (e.g. polycomb modifiers of Aurora A expression [43, 44]). In addition to these traditional modifiers of gene expression, co- and post-transcriptional activities like splicing and RNA degradation also control gene expression and have been linked to genome instability and cancer [45–47].…”

Aurora kinases in head and neck cancer

“…[58] BMI1 supports cancer stem cell renewal and the epithelial-mesenchymal transition (EMT) that often precedes cancer invasion and metastasis. In hypopharyngeal cancer FaDu cells and other SCCHN cell lines, ectopic expression of BMI1 elevated Aurora-A mRNA and protein levels, while the reciprocal was seen following BMI1 knockdown.…”

Deregulation of Bmi-1 is associated with enhanced migration, invasion and poor prognosis in salivary adenoid cystic carcinoma

“…Moreover, Bmi-1 was also found to play a key role in tumor metastasis [13]. Chou found that Bmi-1 overexpression drive stem-like properties associated with the induction of the EMT that promotes migration, invasion and poor prognosis in head and neck cancer [14]. These observations led us to hypothesize that Bmi-1 deregulation may induce migration and invasion of SACC.…”