Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state

Sandro Santagata, Marc L. Mendillo, Yun Chi Tang, Aravind Subramanian, Casey C. Perley, Stéphane P. Roche, Bang Wong, Rajiv Narayan, Hyoungtae Kwon, Martina Koeva, Angelika Amon, Todd R. Golub, John A. Porco, Luke Whitesell*, Susan Lindquist

*Corresponding author for this work

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions.

Original languageEnglish (US)
Article number1238303
JournalScience
Volume341
Issue number6143
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • General

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    Santagata, S., Mendillo, M. L., Tang, Y. C., Subramanian, A., Perley, C. C., Roche, S. P., Wong, B., Narayan, R., Kwon, H., Koeva, M., Amon, A., Golub, T. R., Porco, J. A., Whitesell, L., & Lindquist, S. (2013). Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science, 341(6143), [1238303]. https://doi.org/10.1126/science.1238303