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PNAS 104 (49): 19488-19493

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition

Mikhail A. Nikiforov*,{dagger}, MaryBeth Riblett*,{dagger}, Wen-Hua Tang*,{dagger}, Vladimir Gratchouck*,{dagger}, Dazhong Zhuang*,{dagger}, Yolanda Fernandez*,{dagger},{ddagger}, Monique Verhaegen*,{dagger}, Sooryanarayana Varambally{dagger},§, Arul M. Chinnaiyan{dagger},§, Andrzej J. Jakubowiak§,¶, and Maria S. Soengas*,{dagger},||

Departments of *Dermatology and Internal Medicine, {dagger}Comprehensive Cancer Center, and §Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109

Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved October 3, 2007

Received for publication September 5, 2007.

Abstract: The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1{alpha}, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition.

Key Words: drug selectivity • melanoma • oncogenes • apoptosis • Bcl-2 family

Author contributions: M.A.N. and M.S.S. designed research; M.A.N., M.R., W.-H.T., V.G., D.Z., Y.F., M.V., and M.S.S. performed research; M.A.N., D.Z., S.V., A.M.C., and A.J.J. contributed new reagents/analytic tools; M.A.N. and M.S.S. analyzed data; and M.S.S. wrote the paper.

{ddagger}Present address: Merck KGaA, Bioresearch Laboratory, Parc Científic de Barcelona, 08028 Barcelona, Spain.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0708380104/DC1.

||To whom correspondence should be addressed at: University of Michigan Comprehensive Cancer Center (4217 CCGC), 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: soengas{at}umich.edu

© 2007 by The National Academy of Sciences of the USA

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