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Series GSE14003 Query DataSets for GSE14003
Status Public on Feb 20, 2009
Title ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells
Organism Homo sapiens
Experiment type Expression profiling by array
Summary The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.
Overall design 1. EerI 10 vs 0
2. EerI 10 vs 0
3. Bzm 10 vs 0
4. Bzm 10 vs 0
Contributor(s) Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y
Citation(s) 19164757
Submission date Dec 16, 2008
Last update date Dec 06, 2018
Contact name WeiPing Chen
Phone 301-496-0175
Organization name NIDDK/NIH
Department GCL
Lab Genomics Core Lab
Street address Bldg 8, Room 1A11, NIDDK/NIH
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (8)
GSM350591 06-19-07_Ye_HG-U133A_2_0_B1_0
GSM350592 06-19-07_Ye_HG-U133A_2_0_B1_10
GSM350593 06-19-07_Ye_HG-U133A_2_0_B2_0
BioProject PRJNA111269

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE14003_RAW.tar 25.9 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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