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; Scott M Dehm

doi:10.1038/s41467-021-26612-1

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

Nat Commun. 2021 Nov 4;12(1):6377. doi: 10.1038/s41467-021-26612-1.

Authors

Meixia Che^#¹, Aashi Chaturvedi^#¹, Sarah A Munro^#², Samuel P Pitzen^{1

3}, Alex Ling⁴, Weijie Zhang⁴, Josh Mentzer⁴, Sheng-Yu Ku⁵, Loredana Puca⁶, Yanyun Zhu⁷, Andries M Bergman⁷, Tesa M Severson⁷, Colleen Forster⁸, Yuzhen Liu⁹, Jacob Hildebrand^{1

10}, Mark Daniel^{1

10}, Ting-You Wang¹¹, Luke A Selth^{12

13}, Theresa Hickey¹³, Amina Zoubeidi^{14

15}, Martin Gleave^{14

15}, Rohan Bareja¹⁶, Andrea Sboner¹⁶, Wayne Tilley¹³, Jason S Carroll¹⁷, Winston Tan¹⁸, Manish Kohli¹⁹, Rendong Yang^{1

11}, Andrew C Hsieh⁹, Paari Murugan⁸, Wilbert Zwart⁷, Himisha Beltran⁵, R Stephanie Huang⁴, Scott M Dehm^{20

21

22}

Affiliations

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 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. [email protected].
²¹ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA. [email protected].
²² Department of Urology, University of Minnesota, Minneapolis, MN, 55455, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Line, Tumor
Humans
Kruppel-Like Transcription Factors / metabolism*
Male
Neoplasm Staging
Neuroendocrine Cells / metabolism*
Neuroendocrine Cells / pathology
Prostatic Neoplasms, Castration-Resistant / genetics
Prostatic Neoplasms, Castration-Resistant / metabolism*
Prostatic Neoplasms, Castration-Resistant / pathology
Receptor, ErbB-2 / metabolism*
Receptors, Androgen / metabolism*
Signal Transduction
Transcriptional Activation

Substances

AR protein, human
KLF5 protein, human
Kruppel-Like Transcription Factors
Receptors, Androgen
ERBB2 protein, human
Receptor, ErbB-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding