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

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.

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

“…In line with these results, different animal experiments with genetically modified mice showed an essential role of HSF1 in tumor development (26,27,63) (Table II).…”

“…The expression of HSPs is mainly regulated by HSF1 (17,18). HSPs (12,56,57) as well as HSF1 (19-26) are abundantly expressed in human cancer cells of various origins, and HSPs (12,56,57) and HSF1 (12,(25)(26)(27)(28)(29) play critical roles in the initiation, proliferation and maintenance of cancer. Thus, the combination of HT and HSF1-targeting may be an attractive option and worthy of further investigation.…”

“…It has also been demonstrated that both HSF2 (51) and HSF4 (52) play critical roles in the neural functions or lens development by using HSF2-and HSF4-KO mice. Thus, accumulating evidence suggests that HSFs are closely associated with longevity (53), neurodegenerative diseases (54) and cancer (12,(25)(26)(27)(28)(29). Indeed, HSFs play a versatile role in the organism, from homeostatic maintenance to disease.…”

“…Ishiwata et al (24) reported that higher nuclear HSF1 expression was closely related to tumor size and histopathologic types in OSCCs. Moreover, high expression of HSF1 mRNA in human breast cancer was correlated with grade, metastasis, and poor prognosis, suggesting that HSF1 is involved in tumor progression (26). Mendillo et al (25) identified an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock by using chromatin immunoprecipitation coupled with massively parallel DNA sequencing.…”

“…In mammals, the expression of HSPs is mainly regulated by heat shock transcription factor 1 (HSF1) (17,18). Elevation of HSF1 has been observed in several types of human tumor tissues (19)(20)(21)(22)(23)(24)(25)(26), and it has been shown to participate in the initiation, proliferation and maintenance of tumors (12,(25)(26)(27)(28)(29). Notably, both inhibition of the expression of HSF1 and the functional loss of HSF1 have been suggested to enhance the sensitivity to HT under basic experimental conditions (29)(30)(31)(32)(33)(34)(35)(36)(37)(38).…”