title: Targeting HSF1 sensitizes cancer cells to HSP90 inhibition.
abstract: The molecular chaperone heat shock protein 90 (HSP90) facilitates the appropriate folding of various oncogenic proteins and is necessary for the survival of some cancer cells. HSP90 is therefore an attractive drug target, but the efficacy of HSP90 inhibitor may be limited by HSP90 inhibition induced feedback mechanisms. Through pooled RNA interference screens, we identified that heat shock factor 1(HSF1) is a sensitizer of HSP90 inhibitor. A striking combinational effect was observed when HSF1 knockdown plus with HSP90 inhibitors treatment in various cancer cell lines and tumor mouse models. Interestingly, HSF1 is highly expressed in hepatocellular carcinoma (HCC) patient samples and HCC is sensitive to combinational treatment, indicating a potential indication for the combinational treatment. To understand the mechanism of the combinational effect, we identified that a HSF1-target gene DEDD2 is involved in attenuating the effect of HSP90 inhibitors. Thus, the transcriptional activities of HSF1 induced by HSP90 inhibitors provide a feedback mechanism of limiting the HSP90 inhibitor's activity, and targeting HSF1 may provide a new avenue to enhance HSP90 inhibitors activity in human cancers.
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Yaoyu
authors.initials: Y
authors.lastname: Chen
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.forename: Savina
authors.initials: S
authors.lastname: Jaeger
authors.forename: Linda
authors.initials: L
authors.lastname: Bagdasarian
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yu
authors.forename: Franklin
authors.initials: F
authors.lastname: Chung
authors.forename: Joshua
authors.initials: J
authors.lastname: Korn
authors.forename: David
authors.initials: D
authors.lastname: Ruddy
authors.forename: Ribo
authors.initials: R
authors.lastname: Guo
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin
authors.forename: Fei
authors.initials: F
authors.lastname: Feng
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Frank
authors.initials: F
authors.lastname: Stegmeier
authors.forename: Raymond
authors.initials: R
authors.lastname: Pagliarini
authors.forename: Dale
authors.initials: D
authors.lastname: Porter
authors.forename: Wenlai
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C450835:DEDD2 protein, human; D004268:DNA-Binding Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D004318:Doxycycline