A Pathway for the Control of Anoikis Sensitivity by E-Cadherin and Epithelial-to-Mesenchymal Transition

Abstract

Detachment of epithelial cells from matrix or attachment to an inappropriate matrix engages an apoptotic response known as anoikis, which prevents metastasis. Cellular sensitivity to anoikis is compromised during the oncogenic epithelial-to-mesenchymal transition (EMT), through unknown mechanisms. We report here a pathway through which EMT confers anoikis resistance. NRAGE (neurotrophin receptor-interacting melanoma antigen) interacted with a component of the E-cadherin complex, ankyrin-G, maintaining NRAGE in the cytoplasm. Oncogenic EMT downregulated ankyrin-G, enhancing the nuclear localization of NRAGE. The oncogenic transcriptional repressor protein TBX2 interacted with NRAGE, repressing the tumor suppressor gene p14ARF. P14ARF sensitized cells to anoikis; conversely, the TBX2/NRAGE complex protected cells against anoikis by downregulating this gene. This represents a novel pathway for the regulation of anoikis by EMT and E-cadherin.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01342-10.

ACKNOWLEDGMENTS

We thank Robert Weinberg, Peter Stoilov, Colin Goding, Vann Bennett, Krish Kizhatil, Deborah Anderson, Ken Watanabe, Keith Robertson, Peter Hurlin, Taosheng Huang, James Reecy, Srikumar Othumpangat, Laura Gibson, Lindsay Hinck, Prasad Devarajan, Kathy Brundage, Karen Martin, Mike Ruppert, Sendurai Mani, Richard Myers, and Ned Sharpless for reagents, cell lines, and advice. In particular, we thank Alexey Ivanov for significant technical advice and reagents and Jim Denvir for statistical analyses. We also thank Mike Ruppert and Mike Schaller for critical reading of the manuscript.

S.M.F. was supported by a component of an NIH COBRE grant (P20 RR16440) and by NIH grant R01CA123359. The flow cytometry core facility (Mary Babb Randolph Cancer Center) was supported by NIH grants RR020866 and P20 RR16440.