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

Roger S Smith; Seesha R Takagishi; David R Amici; Kyle Metz; Sitaram Gayatri; Milad J Alasady; Yaqi Wu; Sonia Brockway; Stephanie L Taiberg; Natalia Khalatyan; Mikko Taipale; Sandro Santagata; Luke Whitesell; Susan Lindquist; Jeffrey N Savas; Marc L Mendillo

doi:10.1126/sciadv.abj6526

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

Sci Adv. 2022 Mar 18;8(11):eabj6526. doi: 10.1126/sciadv.abj6526. Epub 2022 Mar 16.

Authors

Roger S Smith^{1

2

3

4}, Seesha R Takagishi^{1

2

3

5

6}, David R Amici^{1

2

3

4}, Kyle Metz^{1

2

3}, Sitaram Gayatri^{1

2

3}, Milad J Alasady^{1

2

3}, Yaqi Wu^{1

2

3

7}, Sonia Brockway^{1

2

3}, Stephanie L Taiberg^{1

2

3}, Natalia Khalatyan^{2

8}, Mikko Taipale^{9

10

11}, Sandro Santagata^{12

13

14}, Luke Whitesell¹⁰, Susan Lindquist^{15

16

17}, Jeffrey N Savas^{2

8}, Marc L Mendillo^{1

2

3}

Affiliations

¹ Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
² Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
³ Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁵ Department of Biochemistry and Biophysics, UCSF, San Francisco, CA 94158, USA.
⁶ Tetrad Graduate Program, UCSF, San Francisco, CA 94143, USA.
⁷ Master of Biotechnology Program, Northwestern University, Evanston, IL 60208, USA.
⁸ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁹ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹¹ Molecular Architecture of Life Program, Canadian Institute for Advanced Research (CIFAR), Toronto, ON, Canada.
¹² Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹³ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
¹⁴ Ludwig Center at Harvard, Boston, MA 02115, USA.
¹⁵ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
¹⁶ Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
¹⁷ Howard Hughes Medical Institute, Cambridge, MA 02139, USA.

Abstract

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 noncanonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no substantial role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have notably similar chromatin occupancy and regulate a common set of genes that include both HSPs and noncanonical 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. Together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state.

Abstract

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