The unfolded protein response (UPR) triggers multiple pathways to allow cells to respond to stress conditions that target the endoplasmic reticulum (ER). The ER is a cellular organelle where secretory and membrane proteins are synthesized and modified and is also a major intracellular calcium storage compartment. The glucose regulated protein GRP78, also referred to as the immunoglobulin binding protein, BiP, is a central regulator for ER function due to its role in protein folding and assembly, targeting misfolded protein for degradation, ER calcium binding and controlling the activation of transmembrane ER stress sensors. The activation of the gene encoding GRP78 (Grp78) is widely used as a monitor for ER stress and has led to the discoveries of several unique signaling pathways whereby stress in this critical organelle is transmitted to the nucleus to initiate the UPR. Further, due to its anti-apoptotic property, stress induction of GRP78 represents an important pro-survival component of the UPR. As a master regulator of ER function, GRP78 is uniquely poised to have a major role in regulating cellular homeostasis and the balance between cancer cell death and aggressive growth, as well as modulating the sensitivity to chemotherapeutic agents. During the past grant period, we discovered that histone deacetylase (HDAC) inhibitors are novel inducers of Grp78 transcription and act synergistically with ER stress inducers resulting in upregulation of GRP78. Since HDAC inhibitors are currently being exploited as a promising new class of anti-cancer agents, we have discovered a novel UPR target affected by these compounds. The central hypothesis of the current proposal is that Grp78 transcription is regulated by the acetylation of chromatin and transcription factors binding to the Grp78 promoter, and that changes in GRP78 expression influence the development of tumors and their responses to therapeutic intervention by HDAC inhibitors. Through genetic targeting, we have created novel mouse models where GRP78 expression is reduced or can be knocked out in specific tissues and this will allow us to test directly the role of GRP78 in the pathogenesis of cancer. We have three specific aims. In Aim 1, we will determine the mechanisms whereby HDAC inhibitors activate Grp78 transcription. In Aim 2, we will determine whether enhanced-induction of GRP78 by HDAC inhibitors currently being tested in clinical trials confers drug resistance in cancer cells through inhibition of apoptosis. In Aim 3, we will determine whether reduction or conditional knockout of GRP78 will lead to suppression of cancer progression and metastasis. If our hypothesis is correct, it will establish GRP78 as a prognostic marker for cancer progression and resistance against HDAC inhibitor therapy. Further, targeted inhibition of GRP78 could be used to halt tumor progression and overcome resistance to HDAC inhibitor therapy.