Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer

Meixia Che, Aashi Chaturvedi, Sarah A. Munro, Samuel P. Pitzen, Alex Ling, Weijie Zhang, Josh Mentzer, Sheng-Yu Ku, Loredana Puca, Yanyun Zhu, Andries M. Bergman, Tesa M. Severson, Colleen Forster, Yuzhen Liu, Jacob Hildebrand, Mark Daniel, Ting-You Wang, Luke A. Selth, Theresa Hickey, Amina Zoubeidi, Martin Gleave, Rohan Bareja, Andrea Sboner, Wayne Tilley, Jason S. Carroll, Winston Tan, Manish Kohli, Rendong Yang, Andrew C. Hsieh, Paari Murugan, Wilbert Zwart, Himisha Beltran, R. Stephanie Huang and Scott M. Dehm ()
Additional contact information
Meixia Che: University of Minnesota
Aashi Chaturvedi: University of Minnesota
Sarah A. Munro: University of Minnesota
Samuel P. Pitzen: University of Minnesota
Alex Ling: University of Minnesota
Weijie Zhang: University of Minnesota
Josh Mentzer: University of Minnesota
Sheng-Yu Ku: Dana Farber Cancer Institute and Harvard Medical School
Loredana Puca: Weill Cornell Medicine
Yanyun Zhu: The Netherlands Cancer Institute
Andries M. Bergman: The Netherlands Cancer Institute
Tesa M. Severson: The Netherlands Cancer Institute
Colleen Forster: University of Minnesota
Yuzhen Liu: Fred Hutchinson Cancer Research Center
Jacob Hildebrand: University of Minnesota
Mark Daniel: University of Minnesota
Ting-You Wang: University of Minnesota
Luke A. Selth: Flinders University
Theresa Hickey: The University of Adelaide
Amina Zoubeidi: University of British Columbia
Martin Gleave: University of British Columbia
Rohan Bareja: Weill Cornell Medicine
Andrea Sboner: Weill Cornell Medicine
Wayne Tilley: The University of Adelaide
Jason S. Carroll: University of Cambridge
Winston Tan: Mayo Clinic
Manish Kohli: University of Utah
Rendong Yang: University of Minnesota
Andrew C. Hsieh: Fred Hutchinson Cancer Research Center
Paari Murugan: University of Minnesota
Wilbert Zwart: The Netherlands Cancer Institute
Himisha Beltran: Dana Farber Cancer Institute and Harvard Medical School
R. Stephanie Huang: University of Minnesota
Scott M. Dehm: University of Minnesota

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26612-1

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