XBP1 is essential for survival under hypoxic conditions and is required for tumor growth.
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.
Romero-Ramirez
Lorenzo
L
Department of Radiation Oncology, Stanford University, Stanford, California 94305-5152, USA.
Cao
Hongbin
H
Nelson
Daniel
D
Hammond
Ester
E
Lee
Ann-Hwee
AH
Yoshida
Hiderou
H
Mori
Kazutoshi
K
Glimcher
Laurie H
LH
Denko
Nicholas C
NC
Giaccia
Amato J
AJ
Le
Quynh-Thu
QT
Koong
Albert C
AC
D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D011905:Genes, ras; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse