HSF1 regulates a cancer-specific transcriptional program that differs from the heat-shock response.
Major finding: HSF1 regulates a cancer-specific transcriptional program that differs from the heat-shock response.
Clinical relevance: The HSF1 gene signature is associated with poor outcome in breast, colon, and lung cancers.
Impact: The role of HSF1 in cancer is not primarily mediated by heat-shock protein chaperone activity.
The heat-shock response is an adaptive mechanism induced in response to environmental stress whereby the transcription factor heat-shock factor 1 (HSF1) activates the expression of chaperones that restore protein homeostasis. HSF1 is also co-opted by cancer cells to support their survival, as human cancer cells have an increased dependence on HSF1 for growth and survival and Hsf1-knockout mice are tumor resistant. However, whether HSF1 indirectly supports cancer progression via chaperone proteins induced by the heat-shock response, as is generally assumed, or has a distinct, cancer-specific role remains unclear. In support of this latter possibility, Mendillo and colleagues observed that HSF1 bound approximately 900 genes in highly malignant transformed mammary epithelial cells, 60% of which were not bound by HSF1 in parental or nontransformed cells, even after heat shock. The canonical heat-shock element was highly enriched in HSF1-bound regions, and HSF1 knockdown markedly affected the expression of HSF1-bound genes in malignant cells, suggesting that HSF1 directly regulates a cancer-specific gene expression program. The distinct HSF1 occupancy pattern observed in genetically engineered cells was conserved across cancer cell lines and clinical samples derived from multiple tumor types, but not nontumorigenic cell lines exposed to heat shock, and the cancer and heat-shock bound regions were enriched for different binding motifs. Notably, HSF1 was highly expressed in clinical samples from a broad range of tumor types, and high expression of a signature of genes bound by HSF1 in cancer cells was predictive of poor outcome among patients with breast, colon, or lung cancers. Together, these findings establish that HSF1 coordinates a transcriptional program in cancer that is distinct from the heat-shock response and may play a broader role in cancer progression than previously appreciated.