The role of HSF2 in human malignancies

The heat shock response (HSR) is an ancient survival mechanism that is conserved from yeast to humans. Heat-Shock Factor 1 (HSF1) is the master regulator of the HSR. Proteotoxic stress activates HSF1 to induce expression of heat shock protein genes, including HSP70 and HSP90, to maintain protein homeostasis. In cancer, HSF1 is highly expressed, drives a distinct transcription program from the HSR, and is associated with poor prognosis. Genes in the HSF1 cancer program are involved in a broad range of cellular activities, including protein folding, but also cell proliferation, cell adhesion, apoptosis, and energy metabolism. To better understand HSF1’s function in cancer cells, we used a multifaceted strategy to identify HSF1-interacting proteins, revealing Heat-Shock Factor 2 (HSF2) as a strong interactor. However, the role of HSF2 in cancer cells and its influence on HSF1 activity has been mostly unexplored. To investigate the function of HSF2 in cancer cells, we integrated ChIP-Seq with RNA-Seq. We found that HSF2 drives a robust transcriptional program in human cancer cell lines. Further, these analyses revealed that HSF2 and HSF1 share a high degree of co-occupancy. Interestingly, we also found that the loss of HSF2 affected HSF1 binding at a subset of sites. Next, we generated ΔHSF2 cell lines derived from single cells and characterized the effects of HSF2 on proliferation, migration and invasion in vitro. We found that the loss of HSF2 affects migration without affecting cancer cell proliferation. Our data suggest that HSF2 plays an important role in human cancers, along with HSF1. Taken together, our data indicate that HSF2 is an important HSF1 cofactor and plays a critical role in mediating carcinogenesis.