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.
Meixia Che1,21, Aashi Chaturvedi1,21, Sarah A. Munro2,21, Samuel P. Pitzen 1,3, Alex Ling 4, Weijie Zhang4, Josh Mentzer4, Sheng-Yu Ku 5, Loredana Puca6, Yanyun Zhu7, Andries M. Bergman 7, Tesa M. Severson7, Colleen Forster8, Yuzhen Liu9, Jacob Hildebrand1,10, Mark Daniel1,10, Ting-You Wang11, Luke A. Selth12,13, Theresa Hickey 13, Amina Zoubeidi 14,15, Martin Gleave14,15, Rohan Bareja16, Andrea Sboner 16, Wayne Tilley 13, Jason S. Carroll 17, Winston Tan18, Manish Kohli19, Rendong Yang 1,11, Andrew C. Hsieh 9, Paari Murugan8, Wilbert Zwart 7, Himisha Beltran5, R. Stephanie Huang 4 & Scott M. Dehm 1,8,20
1 Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. 2 University of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA. 3 Graduate Program in Molecular, Cellular, and Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN 55455, USA. 4 Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. 5 Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA. 6 Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA. 7 Division on Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 8 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. 9 Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. 10 Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, MN 55455, USA. 11 The Hormel Institute, University of Minnesota, Austin, MN 55912, USA. 12 Flinders Health and Medical Research Institute and Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA, Australia. 13 Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men’s Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia. 14 Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada. 15 Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada. 16 Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA. 17 Cancer Research UK, University of Cambridge, CB2 0RE Cambridge, UK. 18 Department of Medicine, Mayo Clinic, Jacksonville, FL 32224, USA. 19 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. 20 Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA. 21These authors contributed equally: Meixia Che, Aashi Chaturvedi, Sarah A. Munro.
Che, M., Chaturvedi, A., Munro, S., Pitzen, S., Ling, A., & Zhang, W. et al. (2021). Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer. Nature Communications, 12(1). doi: 10.1038/s41467-021-26612-1