Active heat shock transcription factor 1 supports migration of the melanoma cells via vinculin down-regulation

Abstract

Heat shock transcription factor 1 (HSF1), the major regulator of stress response, is frequently activated in cancer and has an apparent role in malignant transformation. Here we analyzed the influence of the over-expression of a constitutively active transcriptionally-competent HSF1 mutant form on phenotypes of mouse and human melanoma cells. We observed that the expression of active HSF1 supported anchorage-independent growth in vitro, and metastatic spread in the animal model in vivo, although the proliferation rate of cancer cells was not affected. Furthermore, active HSF1 enhanced cell motility, reduced the adherence of cells to a fibronectin-coated surface, and affected the actin cytoskeleton. We found that although the expression of active HSF1 did not affect levels of epithelial-to-mesenchymal transition markers, it caused transcriptional down-regulation of vinculin, protein involved in cell motility, and adherence. Functional HSF1-binding sites were found in mouse and human Vcl/VCL genes, indicating a direct role of HSF1 in the regulation of this gene. An apparent association between HSF1-induced down-regulation of vinculin, increased motility, and a reduced adherence of cells suggests a possible mechanism of HSF1-mediated enhancement of the metastatic potential of cancer cells.

The Heat Shock Transcription Factor HSF1 Induces Ovarian Cancer Epithelial-Mesenchymal Transition in a 3D Spheroid Growth Model

“…Previous work has shown that cell motility is inhibited in immortalized mouse embryonic fibroblast cells derived from hsf1 -/- mice [25]. In addition, HSF1 knockdown reduces the invasiveness of multiple types of tumor cells [10, 26–29]. Consistent with these findings, we show that HSF1 knockdown inhibits wound healing and cell migration in SKOV3 and HEY ovarian cancer cell lines.…”

Heat shock factor 1 in cancer‐associated fibroblasts is a potential prognostic factor and drives progression of oral squamous cell carcinoma

“…HSF1 activation has been reported as a crucial regulator in the transcriptional reprogramming of the stroma to form a tumor‐supportive environment . Accumulating evidence suggests that HSF1 is overexpressed in various malignant tumors and functions as a potential diagnostic biomarker . Our data show that HSF1 expression in tumor cells was significantly correlated with pathological grade, recurrence and death, and high HSF1 expression in cancer cells had a significantly poor prognostic impact on survival outcomes.…”

“…Moreover, HSF1 is involved in the phosphorylation, nuclear accumulation and trimerization of proteins, and it can bind to HSE to induce the transcription of target genes and participate in many biological processes, including growth, development, survival, and inflammation . However, the activation of HSF1 has been widely correlated with tumor initiation, growth, invasion and metastasis, and HSF1 has been shown to function as a tumor promoter and potential diagnostic biomarker . Recently, there has been growing concern regarding the role of HSF1 in the modulation of the TME.…”

HSF1: Guardian of Proteostasis in Cancer

“…In vivo , HSF1 depletion by RNA interference suppresses growth of human mammary epithelial cells overexpressing HER2 [65], impairs growth, invasion, and metastasis of HCC cells [66,67], and antagonizes growth, invasion, and metastasis of human melanoma cells [68,69]. Conversely, enhanced HSF1 expression promotes in vivo growth, invasion, and metastasis of melanoma cells [43,70,71]. In aggregate, these findings pinpoint HSF1 as a potent pro-oncogenic factor functioning in diverse malignancies.…”