(Conferences / Seminars / Lectures)
Dept. of Physiology Research Seminar: Dr. Marc Mendillo - "Regulation and impact of HSF1 in highly malignant human cancers" more information...
The heat-shock response is an ancient and powerful adaptive mechanism that enables organisms to survive diverse proteotoxic stressors. In mouse models, HSF1 is co-opted by tumor cells to promote their survival, to the detriment of their hosts. The common assumption was that these effects are mediated through regulation of chaperone protein expression. Integrating cell biological, genomic and bioinformatic methods, we reveal a direct and pervasive role for HSF1 in many facets of tumorigenesis, extending far beyond protein folding and stress responses to include cell cycle, apoptosis, energy metabolism and other proliferation-associated processes. We used these data to define an HSF1-regulated expression signature in malignancy and analyzed previously published expression data sets from collections of breast, colon and lung patient tumors with outcome associations. We find that high expression of this HSF1 cancer signature correlates strongly with metastasis and death. Thus, HSF1 engages a regulatory program in the highly malignant state that is distinct from the classic heat-shock response. In a second series of experiments, we used an integrated chemical, genetic and genomic approach and revealed a fundamental link between anabolic cellular processes: protein production, HSF1 activity and energy metabolism. Importantly, exploiting this link with translation initiation inhibitors such as rocaglates selectively impaired the proliferation of neoplastic cells. Moreover, this tight coordination of protein synthesis and HSF1 activation suggests a unifying principle that explains the HSF1 activation we previously observed in the extraordinarily wide range of human cancers.