title: Inhibiting heat shock factor 1 in human cancer cells with a potent RNA aptamer.
abstract: Heat shock factor 1 (HSF1) is a master regulator that coordinates chaperone protein expression to enhance cellular survival in the face of heat stress. In cancer cells, HSF1 drives a transcriptional program distinct from heat shock to promote metastasis and cell survival. Its strong association with the malignant phenotype implies that HSF1 antagonists may have general and effective utilities in cancer therapy. For this purpose, we had identified an avid RNA aptamer for HSF1 that is portable among different model organisms. Extending our previous work in yeast and Drosophila, here we report the activity of this aptamer in human cancer cell lines. When delivered into cells using a synthetic gene and strong promoter, this aptamer was able to prevent HSF1 from binding to its DNA regulation elements. At the cellular level, expression of this aptamer induced apoptosis and abolished the colony-forming capability of cancer cells. At the molecular level, it reduced chaperones and attenuated the activation of the MAPK signaling pathway. Collectively, these data demonstrate the advantage of aptamers in drug target validation and support the hypothesis that HSF1 DNA binding activity is a potential target for controlling oncogenic transformation and neoplastic growth.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America; College of Medicine, Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: H Hans
authors.initials: HH
authors.lastname: Salamanca
authors.affiliation: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
authors.affiliation: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
authors.affiliation: Department of Biological Sciences and the RNA Institute, University at Albany, State University of New York, Albany, New York, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America; Department of Biomedical Engineering, Dongguk University, Seoul, South Korea.
authors.forename: John T
authors.initials: JT
authors.lastname: Lis
mesh_terms: D017209:Apoptosis / Q000235:genetics; D052157:Aptamers, Nucleotide / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics; D006358:Hot Temperature; D006801:Humans; D061986:MCF-7 Cells; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D052157:Aptamers, Nucleotide; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D012313:RNA; D020928:Mitogen-Activated Protein Kinases