Abstract
The epithelial–mesenchymal transition (EMT), one of the main mechanisms underlying development of cancer metastasis, induces stem-like properties in epithelial cells. Bmi1 is a polycomb-group protein that maintains self-renewal, and is frequently overexpressed in human cancers. Here, we show the direct regulation of BMI1 by the EMT regulator, Twist1. Furthermore, Twist1 and Bmi1 were mutually essential to promote EMT and tumour-initiating capability. Twist1 and Bmi1 act cooperatively to repress expression of both E-cadherin and p16INK4a. In patients with head and neck cancers, increased levels of both Twist1 and Bmi1 correlated with downregulation of E-cadherin and p16INK4a, and was associated with the worst prognosis. These results suggest that Twist1-induced EMT and tumour-initiating capability in cancer cells occurs through chromatin remodelling, which leads to unfavourable clinical outcomes.
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Acknowledgements
We would like to thank M. C. Hung (M. D. Anderson Cancer Center) for critical comments on the manuscript. We thank L. E. Huang (University of Utah) for pHA-HIF1α(ΔODD) plasmid. We are grateful to T.Y. Chou and W.Y. Li of the Department of Pathology, Taipei Veterans General Hospital for providing advice on IHC analysis. This work was supported in part by National Science Council grants to M.H.Y. (96-2314-B-075-013 and 97-2314-B-010-003) and K.J.W.(97-2320-B-010-029), National Research Program for Genomic Medicine grants to K.J.W (DOH98-TD-G-111-027 and DOH99-TD-G-111-024); Taipei Veterans General Hospital grants to M.H.Y (VGH 98-C1-050; 98-ER2-008, 99-C1-077 and 99-ER2-007) and K.J.W (99-ER2-009), grants from Ministry of Education, Aim for the Top University Plan to M.H.Y (98A-C-T510 and 99A-C-T509) and to K.J.W (99A-C-T508), National Health Research Institutes grants to K.J.W (NHRI-EX-98-9611BI and NHRI-EX-99-9931BI) and a grant from Department of Health, Center of Excellence for Cancer Research at Taipei Veterans General Hospital (DOH99-TD-C-111-007) to M.H.Y.
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M.H.Y., D.S.S.H. and K.J.W. conceived and designed the experiments. M.H.Y., D.S.S.H., H.J.W., H.Y.L. and W.H.Y. performed the experiments with the assistance of C.H.H for in vivo work. H.W.W. performed the bioinformatics analysis. M.H.Y., D.S.S.H. and K.J.W. analysed the data. M.H.Y. and K.J.W. wrote the paper with the assistance of O.S.K.L. and H.W.W. The treatment and sample collection of head-and-neck cancer patients were performed by S.Y.K., S.K.T., S.Y.C., C.H.T. and M.H.Y.
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Yang, MH., Hsu, DS., Wang, HW. et al. Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition. Nat Cell Biol 12, 982–992 (2010). https://doi.org/10.1038/ncb2099
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DOI: https://doi.org/10.1038/ncb2099
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