Heat shock transcription factor Hsf1 is involved in tumor progression via regulation of hypoxia-inducible factor 1 and RNA-binding protein HuR.
Previously we demonstrated that the heat shock transcription factor Hsf1 is indispensable for transformation of mammary epithelial cells by the Her2 oncogene. Since Hsf1 affects oncogene-induced senescence (OIS), these findings suggest that Hsf1 affects tumor initiation when OIS plays a role. Indeed, here we report that Hsf1 knockout suppressed mammary hyperplasia in Her2-expressing mice and reduced tumor emergence. On the other hand, Hsf1 expression increases with advanced breast cancer, indicating that there is an additional role of Hsf1 in tumor progression. We studied rare tumors that developed in Hsf1-knockout mice and found that these tumors grew slower than tumors in control animals and showed suppressed angiogenesis. Similarly, in the xenograft model, knockdown of Hsf1 suppressed angiogenesis, which was associated with suppression of the HIF-1 pathway. Suppression of HIF-1 was at the level of translation due to downregulation of the RNA-binding protein HuR. Importantly, besides HIF-1, HuR controls translation of other major regulators of cancer progression, many of which were suppressed in Hsf1-knockdown cells. Therefore, in addition to OIS, Hsf1 regulates the HuR-HIF-1 pathway, thus affecting both cancer initiation and progression.
Department of Biochemistry, Boston University Medical School, Boston, Massachusetts, USA. Gabai@bu.edu
Vladimir L
VL
Gabai
Le
L
Meng
Geunwon
G
Kim
Teresa A
TA
Mills
Ivor J
IJ
Benjamin
Michael Y
MY
Sherman
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D016601:RNA-Binding Proteins; D014157:Transcription Factors