Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition.
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-1alpha, 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.
Department of Dermatology, Comprehensive Cancer Center, and Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Mikhail A
MA
Nikiforov
Marybeth
M
Riblett
Wen-Hua
WH
Tang
Vladimir
V
Gratchouck
Dazhong
D
Zhuang
Yolanda
Y
Fernandez
Monique
M
Verhaegen
Sooryanarayana
S
Varambally
Arul M
AM
Chinnaiyan
Andrzej J
AJ
Jakubowiak
Maria S
MS
Soengas
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015195:Drug Design; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D050687:E2F1 Transcription Factor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498702:PMAIP1 protein, human; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib