The ubiquitin-proteasome system 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 endoplasmic reticulum 
(ER)-associated protein degradation, has antitumor and biologic activities 
similar to bortezomib and can synergize with bortezomib. Like bortezomib, 
EerI-induced cytotoxicity requires the up-regulation of the Bcl-2 homology3 
(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 anticancer agents that 
integrate ER stress response with an epigenetic mechanism to induce cell death.