Transcriptional upregulation of HSP70-2 by HIF-1 in cancer cells in response to hypoxia.
Heat shock protein 70-2 (HSP70-2) can be expressed by cancer cells and act as an important regulator of cancer cell growth and survival. Here, we show the molecular mechanisms by which hypoxia regulate HSP70-2 expression in cancer cells. When cells were subjected to hypoxia (1% O2), the expression of HSP70-2 had a significant increase in cancer cells. Such increase was due to the direct binding of hypoxia-inducible factor to hypoxia-responsive elements (HREs) in the HSP70-2 promoter. By luciferase assays, we demonstrated that the HRE1 at position -446 was essential for transcriptional activation of HSP70-2 promoter under hypoxic conditions. We also demonstrated that HIF-1alpha binds to the HSP70-2 promoter and the binding is specific, as revealed by HIF binding/competition and chromatin immunoprecipitation assays. Consequently, the upregulation of HSP70-2 enhanced the resistance of tumor cells to hypoxia-induced apoptosis. These findings provide a new insight into how tumor cells overcome hypoxic stress and survive, and also disclose a new regulatory mechanism of HSP70-2 expression in tumor cells.
Huang
Wen-Jie
WJ
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, and Division of Gastroenterology, Tongji Hospital, Wuhan, Hubei Province, People's Republic of China.
Xia
Li-Min
LM
Zhu
Fan
F
Huang
Bo
B
Zhou
Chun
C
Zhu
Hui-Fen
HF
Wang
Bo
B
Chen
Bin
B
Lei
Ping
P
Shen
Guan-Xin
GX
D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D018450:Disease Progression; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding
C497442:HIF1A protein, human; D018840:HSP70 Heat-Shock Proteins; C525621:HSPA1B protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit