Blog: Decoding the Research

New role for Heat-Shock Factor 1 as master regulator promoting cancer malignancy

Published: August 3rd, 2012

Researchers at the Whitehead Institute have uncovered a new role for Heat-Shock Factor 1 (HSF1) as a master regulator of many cellular pathways promoting cancer malignancy. This research identifies a new target that can help predict patient responses to treatment and patient outcomes, in addition to guiding future drug development across multiple cancers including lung, breast and colon cancers.

Cells have maintenance and repair systems to protect against various kinds of stress (such as heat or oxidative stress) that can severely damage proteins. Proteins interact with each other based on shape, like puzzle pieces fitting together. When exposed to stress (for example, high temperatures) proteins can denature and become unfolded. Heat shock proteins (also called “chaperones”) help proteins that have become denatured or otherwise modified get back to their normal shape, interact with the right protein partners, and keep the cell up and running.

Cancer cells use heat shock proteins to protect against stresses that would normally be catastrophic and cause death, making them attractive drug targets. For example, Uniting Against Lung Cancer previously funded Dr. Lee Krug (Memorial Sloan-Kettering Cancer Center) to conduct preclinical and clinical testing of a heat-shock protein inhibitor in lung cancer. While the result of that study was negative, there are a number of ongoing clinical trials testing other inhibitors of heat-shock proteins in lung and other cancers.

HSF1 is a master regulator of the heat-shock response, this new research shows HSF1 plays an even larger role in protecting cells from stress, and can potentially “rewire” the cell to promote malignancy.  Mendillo et al. found that HSF1 can influence not only the heat shock response, but also additional cancer-promoting processes including transcription (DNA ® RNA), translation (RNA ® proteins), DNA repair, cell cycle progression, energy metabolism, cell adhesion, cell death, immune responses, and development.

Researchers and doctors can use this information in two ways. First, we can look at HSF1 in a patient’s tumor to predict outcomes and response to treatment. Lung, breast and colon tumor cells had increased levels and activation of HSF1, and this increase was correlated with poorer outcomes. Second, researchers now have a new target with far-reaching implications in cancer cells. Knowing that HSF1 has wide-ranging effects on the cell will help guide future drug development. HSF1 is a transcription factor, meaning it travels to the nucleus of the cell and binds DNA to activate certain genes. We haven’t yet figured out how to directly inhibit transcription factors (unlike kinases or other surface proteins), but we may be able to indirectly affect HSF1 by attacking from other angles.

Reference:

Mendillo ML et. al. HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers. Cell, 2012; 150 (3): 549 DOI: 10.1016/j.cell.2012.06.031.