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.

BACKGROUND: Patterns of global histone modifications have been suggested to be predictors of clinical outcome in many cancers. However, the role of global histone modification patterns in oral squamous cell carcinoma (OSCC) is unclear. METHODS: A retrospective clinicopathologic analysis was undertaken of 186 patients with oral squamous cell carcinoma who received complete ablative surgical treatment. Tissue arrays were made from those paraffin-embedded OSCC samples and examined by immunohistochemistry for histone 3 lysine 4 acetylation (H3K4ac), histone 3 lysine 18 acetylation (H3K18ac), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3). RESULTS: A low level of H3K4ac and a high level of H3K27me3 were associated with advanced T status, N status, tumor stage, and perineural invasion. They were also correlated with cancer-specific survival (CSS) and disease-free survival (DFS). The 5-year CSS and DFS in H3K4ac low vs. H3K4ac high were 74.8% versus 92.5% (P 5.010), and 51.4% versus 76.2% (P 5.001), respectively. The 5-year CSS and DFS in H3K27me3 low versus H3K27me3 high were 94.7% versus 62.3% (P <.001) and 76.4% versus 32.3% (P <.001), respectively. We also found improved prediction for DFS after combining the H3K4ac low and H3K27me3 high profiles and comparing the scores with the other modification patterns (P <.0001). CONCLUSIONS: This research demonstrates the potential prognostic utility of global histone modification analysis for OSCC. Cancer 2013;119:4259-67. V C 2013 American Cancer Society.KEYWORDS: histone modification, oral squamous cell carcinoma, prognosis. INTRODUCTIONOral squamous cell carcinoma (OSCC) is one of the most distressing diseases worldwide and is characterized by high localregional recurrence and poor long-term survival rates. The most decisive factors affecting the prognosis of patients with OSCC are the nodal status and the stage of the disease. Despite advancements made in the field of oral cancer early detection and multimodality treatment according to different clinicopathologic prognosticators, there has only been minor improvement in the response rate to current therapeutic strategies, particularly for tumors diagnosed in advanced stages. 1 There are likely substantial prognostic factors at the molecular level that contribute to the biological behavior of the tumors.Cancer is now considered a disease of genetic and epigenetic alterations. 2 Evidence has shown that the accumulation of a wide range of both genetic and epigenetic alterations in a multistep process promotes tumorigenesis and cancer progression. Genetic alterations are irreversible changes in a DNA sequence that can lead to either oncogene activation or tumorsuppressor gene inactivation. 3 In contrast, epigenetic changes are heritable and potentially reversible modifications in gene expression that occur without alterations to the DNA sequence. 4 In the past decade, epigenetic alterations, which include DNA methylation, the modifi...