title: Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.forename: Marc L
authors.initials: ML
authors.lastname: Mendillo
authors.forename: Yun-chi
authors.initials: YC
authors.lastname: Tang
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.forename: Casey C
authors.initials: CC
authors.lastname: Perley
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Roche
authors.forename: Bang
authors.initials: B
authors.lastname: Wong
authors.forename: Rajiv
authors.initials: R
authors.lastname: Narayan
authors.forename: Hyoungtae
authors.initials: H
authors.lastname: Kwon
authors.forename: Martina
authors.initials: M
authors.lastname: Koeva
authors.forename: Angelika
authors.initials: A
authors.lastname: Amon
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004734:Energy Metabolism / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D000076249:Heat Shock Transcription Factors; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; C107772:rocaglamide