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 thatATF3 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 in cancer cells.