Hypoxia within solid tumors is a major determinant of outcome after anticancer therapy. Analysis of gene expression changes during hypoxia indicated that unfolded protein response genes were one of the most robustly induced groups of genes. In this study, we investigated the hypoxic regulation of X-box binding protein (XBP1), a major transcriptional regulator of the unfolded protein response. Hypoxia induced XBP1 at the transcriptional level and activated splicing of its mRNA, resulting in increased levels of activated XBP1 protein. After exposure to hypoxia, apoptosis increased and clonogenic survival decreased in XBP1-deficient cells. Loss of XBP1 severely inhibited tumor growth due to a reduced capacity for these transplanted tumor cells to survive in a hypoxic microenvironment. Taken together, these studies directly implicate XBP1 as an essential survival factor for hypoxic stress and tumor growth.
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