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

Author

Listed:
  • Meixia Che

    (University of Minnesota)

  • Aashi Chaturvedi

    (University of Minnesota)

  • Sarah A. Munro

    (University of Minnesota)

  • Samuel P. Pitzen

    (University of Minnesota
    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
    University of Minnesota)

  • Mark Daniel

    (University of Minnesota
    University of Minnesota)

  • Ting-You Wang

    (University of Minnesota)

  • Luke A. Selth

    (Flinders University
    The University of Adelaide)

  • Theresa Hickey

    (The University of Adelaide)

  • Amina Zoubeidi

    (University of British Columbia
    Vancouver Prostate Centre)

  • Martin Gleave

    (University of British Columbia
    Vancouver Prostate Centre)

  • 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
    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
    University of Minnesota
    University of Minnesota)

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.

Suggested Citation

  • 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, 2021. "Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26612-1
    DOI: 10.1038/s41467-021-26612-1
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    References listed on IDEAS

    as
    1. Baotong Zhang & Yixiang Li & Qiao Wu & Lin Xie & Benjamin Barwick & Changying Fu & Xin Li & Daqing Wu & Siyuan Xia & Jing Chen & Wei Ping Qian & Lily Yang & Adeboye O. Osunkoya & Lawrence Boise & Paul, 2021. "Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    2. Baotong Zhang & Xinpei Ci & Ran Tao & Jianping Jenny Ni & Xiaoyan Xuan & Jamie L. King & Siyuan Xia & Yixiang Li & Henry F. Frierson & Dong-Kee Lee & Jianming Xu & Adeboye O. Osunkoya & Jin-Tang Dong, 2020. "Klf5 acetylation regulates luminal differentiation of basal progenitors in prostate development and regeneration," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Haiyang Guo & Xinpei Ci & Musaddeque Ahmed & Junjie Tony Hua & Fraser Soares & Dong Lin & Loredana Puca & Aram Vosoughi & Hui Xue & Estelle Li & Peiran Su & Sujun Chen & Tran Nguyen & Yi Liang & Yuzhe, 2019. "ONECUT2 is a driver of neuroendocrine prostate cancer," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    4. Loredana Puca & Rohan Bareja & Davide Prandi & Reid Shaw & Matteo Benelli & Wouter R. Karthaus & Judy Hess & Michael Sigouros & Adam Donoghue & Myriam Kossai & Dong Gao & Joanna Cyrta & Verena Sailer , 2018. "Patient derived organoids to model rare prostate cancer phenotypes," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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    Cited by:

    1. Pamela X. Y. Soh & Naledi Mmekwa & Desiree C. Petersen & Kazzem Gheybi & Smit van Zyl & Jue Jiang & Sean M. Patrick & Raymond Campbell & Weerachai Jaratlerdseri & Shingai B. A. Mutambirwa & M. S. Rian, 2023. "Prostate cancer genetic risk and associated aggressive disease in men of African ancestry," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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