{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:25:22Z","timestamp":1791433522920,"version":"4.3.3"},"reference-count":46,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6143","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2013,7,19]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Ribosome biogenesis is commonly up-regulated to satisfy the increased anabolic demands associated with malignant transformation and tumor growth. Many different oncogenic signaling pathways converge on the ribosome to increase translational flux. Despite the detailed understanding of ribosome regulation in cancer, it is not clear whether the net translational activity of the ribosome can itself regulate transcriptional programs that support and promote the malignant state.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate the transcriptional effects of modulating translational activity in malignant cells, we used integrated chemical and genetic approaches, including a gene signature\u2013based genetic and chemical screen of more than 600,000 gene expression profiles (LINCS database) and an independent, reporter-based chemical screen of more than 300,000 compounds. A lead compound was tested in several cell-lines unified by their increased dependence on HSF1 activation for growth and survival, and in an in vivo cancer model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Inhibiting translation led to large changes in the transcriptome. The single most enriched category consisted of genes regulated by the heat-shock transcription factor, HSF1. The most down-regulated mRNA was\n                      <jats:italic>HSPA8<\/jats:italic>\n                      , which encodes the constitutive HSP70 chaperone that helps to fold nascent polypeptides. The expression of many other genes that HSF1 coordinates to support cancer were also strongly affected. HSF1 protein levels were unchanged, but HSF1 DNA occupancy was nearly eliminated. Inhibition of the HSF1-regulated gene expression program is thus a dominant transcriptional effect elicited by inhibiting protein translation.\n                    <\/jats:p>\n                    <jats:p>Using a gene signature of HSF1 inactivation to query the LINCS database revealed a strong connection between HSF1 inactivation and perturbations that inhibit protein translation, including a broad spectrum of chemical and genetic interventions that target the ribosome, eukaryotic initiation factors (eIFs), aminoacyl tRNA synthetases, and upstream signaling\/regulatory pathways that control translation.<\/jats:p>\n                    <jats:p>Our high-throughput small-molecule screen identified rocaglamide A, an inhibitor of translation initiation, was the strongest inhibitor of HSF1 activation. An analog of this compound, RHT, increased thioredoxin-interacting protein (TXNIP) mRNA and protein levels and decreased glucose uptake and lactate production. Cell-based cancer models characterized by high dependence on HSF1 activation for growth and survival were highly sensitive to RHT, as were cells derived from diverse hematopoietic malignancies. RHT had a strong antitumor effect\u2014with marked inhibition of HSF1 activity and glucose uptake\u2014against xenografted acute myeloid leukemia cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The ribosome functions as a central information hub in malignant cells: Translational flux conveys information about the cell\u2019s metabolic status to regulate the transcriptional programs that support it. Multiple unbiased chemical and genetic approaches establish HSF1 as a prime transducer of this information, centrally poised to regulate the transcription of genes that support protein folding, biomass expansion, anabolic metabolism, cellular proliferation, and survival. Targeting translation initiation may offer a strategy for reversing HSF1 activation, disabling metabolic and cytoprotective pathways in malignant cells.<\/jats:p>\n                    <jats:boxed-text content-type=\"abstract-figure\" orientation=\"portrait\" position=\"float\">\n                      <jats:caption>\n                        <jats:p content-type=\"abstract-graphic\">\n                          <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"341_1238303_Fa.jpeg\"\/>\n                        <\/jats:p>\n                        <jats:p content-type=\"abstract-caption\">\n                          <jats:bold>HSF1 at the crossroads of protein translation and metabolism.<\/jats:bold>\n                          (\n                          <jats:bold>Left<\/jats:bold>\n                          ) Cancers activate an HSF1-regulated transcriptional program to adapt to the anabolic demands of relentless biomass expansion. Glucose uptake increases, and expression of TXNIP, an inhibitor of glucose uptake, drops. (\n                          <jats:bold>Right<\/jats:bold>\n                          ) Down-regulating translation with rocaglate scaffold initiation inhibitors reverses cancer-associated HSF1 activation. Glucose uptake drops as TXNIP levels rise.\n                        <\/jats:p>\n                      <\/jats:caption>\n                    <\/jats:boxed-text>\n                  <\/jats:sec>","DOI":"10.1126\/science.1238303","type":"journal-article","created":{"date-parts":[[2013,7,18]],"date-time":"2013-07-18T14:16:39Z","timestamp":1374156999000},"source":"Crossref","is-referenced-by-count":271,"title":["Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State"],"prefix":"10.1126","volume":"341","author":[{"given":"Sandro","family":"Santagata","sequence":"first","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital (BWH), and Harvard Medical School, Boston, MA 02215, USA."},{"name":"Dana Farber Cancer Institute, Boston, MA 02215, USA."},{"name":"Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc L.","family":"Mendillo","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA."},{"name":"Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-chi","family":"Tang","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA."},{"name":"David H. Koch Institute for Integrative Cancer Research and Howard Hughes Medical Institute, MIT, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravind","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey C.","family":"Perley","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA."},{"name":"Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane P.","family":"Roche","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bang","family":"Wong","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Narayan","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoungtae","family":"Kwon","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA."},{"name":"Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Koeva","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA."},{"name":"Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Amon","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA."},{"name":"David H. Koch Institute for Integrative Cancer Research and Howard Hughes Medical Institute, MIT, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd R.","family":"Golub","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"John A.","family":"Porco","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Whitesell","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Lindquist","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA."},{"name":"Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1015"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2001754"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1551"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.23.8862-8877.2003"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2824"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a012252"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1068408"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.06.031"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728220902832697"},{"key":"e_1_3_2_11_2","first-page":"2651","article-title":"Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model","volume":"118","author":"Bordeleau M. 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