The Role of HSF2 in Human Malignancies

Abstract

Heat‐Shock Factor 1 (HSF1) is the master transcriptional regulator of the heat shock response (HSR), an ancient survival mechanism that is conserved from yeast to humans. In 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, and drives a transcriptional program distinct from the HSR. Genes in the HSF1 cancer program are involved in a broad range of cellular activities that include protein folding, but also include cell proliferation, cell adhesion, apoptosis, and energy metabolism. To better understand HSF1 function in cancer cells, we used a multifaceted strategy to identify HSF1‐interacting proteins. We found that Heat‐Shock Factor 2 (HSF2), an HSF1 paralog, was among the strongest HSF1 interacting proteins. However, the role of HSF2 in cancer cells and its influence on HSF1 activity is not well understood. We performed RNA‐Seq and ChIP‐Seq to identify the HSF2 cancer program. We used CRISPR‐Cas9 mediated genome editing to knock out HSF2 and HSF1 in a diverse panel of common human cancer cell lines. We found that HSF2 and HSF1 exhibit distinctive effects on transcription, despite sharing a high degree of genomic co‐occupancy. These transcriptional effects were affected by the type of cancer cell line. Lastly, we characterized the HSF2 cancer phenotype in vitro and in vivo. In vitro, we found that the loss of HSF2 affects cell migration and invasion. In vivo, loss of HSF2 affects tumor formation and growth. Our findings suggest a complex interplay between HSF1 and HSF2 that ultimately impacts malignant progression.Support or Funding InformationNIH/NCI R00 CA175293‐03, Kimmel Scholars Program SKF‐16‐135, Lynn Sage FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.