March 2022

TRANSCRIPTION FACTORS COOPERATE TO PROMOTE CANCER GROWTH

Featuring: Marc Mendillo, PhD

Scientists have discovered that a well-established cancer cell transcription factor and its newly identified co-factor work together to drive cancer cell proliferation, according to findings published in Science Advances.

The team, led by Marc Mendillo, PhD, assistant professor of Biochemistry and Molecular Genetics, found that heat shock factor 2 (HSF2) interacts with its paralog, heat shock factor 1 (HSF1), to drive gene transcription programming in cancerous cells across different subtypes of cancers, promoting tumor progression.

“This helps us understand how this ancient factor really functions in cancer and how it’s important for cancer cell proliferation, and we think it’s going to be important for how cancer cells deal with therapeutics,” said Mendillo, who is also member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

HSF1 is a transcription factor that induces a cell’s heat shock response. This powerful and highly conserved stress response program increases the number of helper proteins called heat shock proteins which protect cells from different environmental stressors, such as those that accompany increased temperature and a variety of toxins.

Previous work has also found that HSF1 contains neuroprotective properties, protecting neurons from cell death caused by the accumulation of misfolded proteins by stimulating the heat shock response.

In the context of cancer cells, however, Mendillo’s group had previously established HSF1 as a key player in cancer cell proliferation, specifically how it drives a distinct gene expression program in cancer cells to support tumor formation and growth. However, the mechanisms by which the transcription factor regulates this transcriptional programing remained poorly understood.

In the current study, Mendillo’s team performed high-throughput screening of more than 2,800 genes and discovered that the HSF2 — which plays no significant role in the heat stress response — interacts with HSF1 to also support cancer cell gene expression programs.

“While HSF1 has been studied extensively in cancer and many other diseases, HSF2 has largely been overlooked — likely because it does not have a major role in the heat shock,” Mendillo said.

HSF1 and HSF2 occupy the same chromatin landscape, which allows HSF2 to bind to HSF1 and regulate a common set of genes containing both heat stress proteins and gene transcription targets, both of which are critical for allowing cancer cells to proliferate and invade other parts of the body.

The investigators also studied cancer cell lines and found that the loss of either HSF1 or HSF2 caused dysregulated gene expression to cope with an insufficient supply of nutrients and reduced tumor progression in vitro.

Mendillo said his team is now interested in identifying strategies to selectively disable this cancer programming while preserving the cytoprotective properties of the heat shock proteins, as well as defining the mechanisms by which HSF1 and HSF2 switch between cytoprotective programming to aggressive cancer programming.

“We know that this is going be important for evading the response to therapy and we’re interested in studying that process very specifically, including investigating how different stress response programs may be connected,” Mendillo said.

Roger Smith, a fourth-year student in the Medical Scientist Training Program (MSTP), was a co-first author of the study. Co-authors include David Amici, a third-year MSTP student; Natalia Khalatyan a third-year student in the Driskill Graduate Program in Life Sciences (DGP); and Jeffrey Savas, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology Division of Behavioral Neurology, of Medicine in the Division of Nephrology and Hypertension and of Pharmacology.

This work was supported by ARCS Foundation Illinois Chapter Scholar Award; National Institutes of Health grants T32GM008152, F30CA264513 and T32GM008152; National Cancer Institute grant R00CA175293; Susan G. Komen Foundation grant CCR17488145; Kimmel Scholar award SKF-16-135; Lynn Sage Scholar awards; and W81XWH-19-1-0627.

This article was originally published in the Feinberg School of Medicine News Center on March 16, 2022.

Marc Mendillo, PhD, assistant professor of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was senior author of the study published in Science Advances.