1. Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer
- Author
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Sheng-Yu Ku, Theresa E. Hickey, Mark Daniel, Andries M. Bergman, Scott M. Dehm, Wilbert Zwart, Martin E. Gleave, Yuzhen Liu, Paari Murugan, Jason S. Carroll, Rendong Yang, Tesa M. Severson, Amina Zoubeidi, Samuel P. Pitzen, Colleen L. Forster, Manish Kohli, R. Stephanie Huang, Aashi Chaturvedi, Luke A. Selth, Loredana Puca, Andrea Sboner, Meixia Che, Josh Mentzer, Andrew C. Hsieh, Wayne D. Tilley, Ting-You Wang, Himisha Beltran, Winston Tan, Rohan Bareja, Alexander Ling, Sarah A. Munro, Jacob Hildebrand, Yanyun Zhu, Weijie Zhang, Pitzen, Samuel P [0000-0001-6556-0461], Ling, Alex [0000-0001-6194-9875], Ku, Sheng-Yu [0000-0003-4715-1888], Bergman, Andries M [0000-0001-5223-2549], Hickey, Theresa [0000-0002-2752-730X], Zoubeidi, Amina [0000-0002-0498-142X], Sboner, Andrea [0000-0001-6915-3070], Tilley, Wayne [0000-0003-1893-2626], Carroll, Jason S [0000-0003-3643-0080], Yang, Rendong [0000-0002-9512-2240], Hsieh, Andrew C [0000-0002-0897-1050], Zwart, Wilbert [0000-0002-9823-7289], Huang, R Stephanie [0000-0002-9862-0368], Dehm, Scott M [0000-0002-7827-5579], Apollo - University of Cambridge Repository, and Carroll, Jason [0000-0003-3643-0080]
- Subjects
Male ,Transcriptional Activation ,Receptor, ErbB-2 ,Science ,Kruppel-Like Transcription Factors ,General Physics and Astronomy ,13/106 ,13/109 ,Biology ,urologic and male genital diseases ,General Biochemistry, Genetics and Molecular Biology ,13/1 ,Prostate cancer ,Neuroendocrine Cells ,42/44 ,Prostate ,Cell Line, Tumor ,38/89 ,13/105 ,Transcription factors ,medicine ,Humans ,631/45/612/822 ,Transcription factor ,Neoplasm Staging ,45/91 ,Multidisciplinary ,Oncogene ,article ,Cell migration ,General Chemistry ,45/15 ,medicine.disease ,Chromatin ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,Receptors, Androgen ,Cancer research ,38/39 ,631/67/589/466 ,Stem cell ,Signal Transduction - 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., While many treatments for prostate cancer suppress the androgen receptor it becomes reactivated during disease progression. Here, the authors show that a KLF5 transcriptional programme is also activated during treatment and promotes migration and the appearance of a basal cell phenotype.
- Published
- 2021