Regulation of transcription of hypoxia-inducible factor-1α (HIF-1α) by heat shock factors HSF2 and HSF4

Abstract

Hypoxia-inducible factor-1a (HIF-1a) is a principal regulator of angiogenesis and other cellular responses to hypoxic stress in both normal and tumor cells. To identify novel mechanisms that regulate expression of HIF-1a, we designed a genome-wide screen for expressed sequence tags (ESTs) that when transcribed in the antisense direction increase production of the HIF-1a target, vascular endothelial growth factor (VEGF), in human breast cancer cells. We discovered that heat shock factor (HSF) proteins 2 and 4-which previously have been implicated in the control of multiple genes that modulate cell growth and differentiation and protect against effects of environmental and cellular stresses-function together to maintain a steady state level of HIF-1a transcription and VEGF production in these cells. We show both HSFs bind to discontinuous heat shock element (HSE) sequences we identified in the HIF-1a promoter region and that downregulation of either HSF activates transcription of HIF-1a. We further demonstrate that HSF2 and HSF4 displace each other from HSF/HSE complexes in the HIF-1a promoter so that HIF-1a transcription is also activated by overexpression of either HSFs. These results argue that HSF2 and HSF4 regulate transcription of HIF-1a and that a critical balance between these HSF is required to maintain HIF-a expression in a repressed state. Our findings reveal a previously unsuspected role for HSFs in control of VEGF and other genes activated by canonical HIF-1a-mediated signaling.

Heat Shock Transcription Factor Hsf1 Is Involved in Tumor Progression via Regulation of Hypoxia-Inducible Factor 1 and RNA-Binding Protein HuR

“…For example, it has been demonstrated in Drosophila that hypoxia induces heat shock response via HIF-1 (3). On the other hand, in mammalian cells Hsf2 and Hsf4 were shown to regulate HIF-1 transcription (10).…”

Metabolic Adaptation to Chronic Inhibition of Mitochondrial Protein Synthesis in Acute Myeloid Leukemia Cells

“…Reported regulators of HIF1α mRNA expression include NF-κB, homeodomain-interacting protein kinase-2 (HIPK2), and heat shock factor proteins 2 and 4 [35], [36], [37]. Further studies will be necessary to understand the mechanism by which HIF1α mRNA is upregulated in the tigecycline resistant cells.…”

Heat shock factor 2 is required for maintaining proteostasis against febrile-range thermal stress and polyglutamine aggregation

“…Cooperative regulation of other targets by HSF family members was also suggested by the fact that mouse HSF4 competes with HSF1 on the expression of fibroblast growth factor 7 in the lens (Fujimoto et al , 2004), and a substantial number of HSF4-binding regions (70%) are cooccupied by HSF1 and HSF2 (Fujimoto et al , 2008). Furthermore, both HSF2 and HSF4 are suggested to regulate the expression of hypoxia-inducible factor-1α in human cells (Chen et al , 2011). Because every member of the HSF family can bind to the HSE consensus sequence, we can state that the HSE-mediated pathways might regulate the expression of HSPs and non-HSP proteins that control proteostasis capacity.…”