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Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.
Che, Meixia; Chaturvedi, Aashi; Munro, Sarah A; Pitzen, Samuel P; Ling, Alex; Zhang, Weijie; Mentzer, Josh; Ku, Sheng-Yu; Puca, Loredana; Zhu, Yanyun; Bergman, Andries M; Severson, Tesa M; Forster, Colleen; Liu, Yuzhen; Hildebrand, Jacob; Daniel, Mark; Wang, Ting-You; Selth, Luke A; Hickey, Theresa; Zoubeidi, Amina; Gleave, Martin; Bareja, Rohan; Sboner, Andrea; Tilley, Wayne; Carroll, Jason S; Tan, Winston; Kohli, Manish; Yang, Rendong; Hsieh, Andrew C; Murugan, Paari; Zwart, Wilbert; Beltran, Himisha; Huang, R Stephanie; Dehm, Scott M.
Afiliación
  • Che M; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Chaturvedi A; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Munro SA; University of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Pitzen SP; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Ling A; Graduate Program in Molecular, Cellular, and Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Zhang W; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Mentzer J; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Ku SY; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Puca L; Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
  • Zhu Y; Division of Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.
  • Bergman AM; Division on Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Severson TM; Division on Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Forster C; Division on Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Liu Y; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Hildebrand J; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • Daniel M; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Wang TY; Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Selth LA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Hickey T; Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Zoubeidi A; The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
  • Gleave M; Flinders Health and Medical Research Institute and Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA, Australia.
  • Bareja R; Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
  • Sboner A; Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
  • Tilley W; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
  • Carroll JS; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada.
  • Tan W; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
  • Kohli M; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada.
  • Yang R; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
  • Hsieh AC; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
  • Murugan P; Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
  • Zwart W; Cancer Research UK, University of Cambridge, CB2 0RE, Cambridge, UK.
  • Beltran H; Department of Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA.
  • Huang RS; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
  • Dehm SM; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
Nat Commun ; 12(1): 6377, 2021 11 04.
Article en En | MEDLINE | ID: mdl-34737261
ABSTRACT
Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Receptor ErbB-2 / Factores de Transcripción de Tipo Kruppel / Células Neuroendocrinas / Neoplasias de la Próstata Resistentes a la Castración Tipo de estudio: Prognostic_studies Límite: Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Receptor ErbB-2 / Factores de Transcripción de Tipo Kruppel / Células Neuroendocrinas / Neoplasias de la Próstata Resistentes a la Castración Tipo de estudio: Prognostic_studies Límite: Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos