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Heat shock transcription factor Hsf1 is involved in tumor progression via regulation of hypoxia-inducible factor 1 and RNA-binding protein HuR. Mol Cell Biol 2012 Mar;32(5):929-40

Date

01/05/2012

Pubmed ID

22215620

Pubmed Central ID

PMC3295200

DOI

10.1128/MCB.05921-11

Scopus ID

2-s2.0-84857169594   60 Citations

Abstract

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.

Author List

Gabai VL, Meng L, Kim G, Mills TA, Benjamin IJ, Sherman MY

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Line, Tumor
Cell Transformation, Neoplastic
Cellular Senescence
DNA-Binding Proteins
Female
Gene Expression Regulation, Neoplastic
Genes, erbB-2
Heat Shock Transcription Factors
Heat-Shock Proteins
Humans
Hypoxia-Inducible Factor 1
Mice
Mice, Knockout
Neoplasm Transplantation
Neoplasms, Experimental
Neovascularization, Pathologic
RNA-Binding Proteins
Transcription Factors
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a