HSF2 cooperates with HSF1 to drive a transcriptional program critical for the malignant state

Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many non-canonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no significant role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have strikingly similar chromatin occupancy and regulate a common set of genes which include both HSPs and non-canonical transcriptional targets with roles critical in supporting malignancy. Loss of either HSF1 or HSF2 results in a dysregulated response to nutrient stresses in vitro and reduced tumor progression in cancer cell line xenografts. Taken together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state. Chromatin occupancy of HSF1 and HSF2 was measured in two cancer cell lines by ChIP-seq. Gene expression profiles were obtained from a panel of cancer cell lines with HSF1 or HSF2 depletion by siRNA or CRISPR/Cas9 gene editing. Gene expression profiles were also obtained from tumors resulting from implantation of HSF1 or HSF2 knockout cancer cell lines in immunocompromised mice.