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

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 ZoubeidiMartin 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^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English (US)
Article number	6377
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26612-1
State	Published - Dec 2021

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Che, M., Chaturvedi, A., Munro, S. A., Pitzen, S. P., Ling, A., Zhang, W., Mentzer, J., Ku, S. Y., Puca, L., Zhu, Y., Bergman, A. M., Severson, T. M., Forster, C., Liu, Y., Hildebrand, J., Daniel, M., Wang, T. Y., Selth, L. A., Hickey, T., ... Dehm, S. M. (2021). Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer. Nature communications, 12(1), Article 6377. https://doi.org/10.1038/s41467-021-26612-1

@article{c45d4a9deaa84ed38444cb116df21d72,

title = "Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer",

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 Kr{\"u}ppel-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.",

author = "Meixia Che and Aashi Chaturvedi and Munro, {Sarah A.} and Pitzen, {Samuel P.} and Alex Ling and Weijie Zhang and Josh Mentzer and Ku, {Sheng Yu} and Loredana Puca and Yanyun Zhu and Bergman, {Andries M.} and Severson, {Tesa M.} and Colleen Forster and Yuzhen Liu and Jacob Hildebrand and Mark Daniel and Wang, {Ting You} and Selth, {Luke A.} and Theresa Hickey and Amina Zoubeidi and Martin Gleave and Rohan Bareja and Andrea Sboner and Wayne Tilley and Carroll, {Jason S.} and Winston Tan and Manish Kohli and Rendong Yang and Hsieh, {Andrew C.} and Paari Murugan and Wilbert Zwart and Himisha Beltran and Huang, {R. Stephanie} and Dehm, {Scott M.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-26612-1",

language = "English (US)",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Che, M, Chaturvedi, A, Munro, SA, Pitzen, SP, Ling, A, Zhang, W, Mentzer, J, Ku, SY, Puca, L, Zhu, Y, Bergman, AM, Severson, TM, Forster, C, Liu, Y, Hildebrand, J, Daniel, M, Wang, TY, Selth, LA, Hickey, T, Zoubeidi, A, Gleave, M, Bareja, R, Sboner, A, Tilley, W, Carroll, JS, Tan, W, Kohli, M, Yang, R, Hsieh, AC, Murugan, P, Zwart, W, Beltran, H, Huang, RS & Dehm, SM 2021, 'Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer', Nature communications, vol. 12, no. 1, 6377. https://doi.org/10.1038/s41467-021-26612-1

TY - JOUR

T1 - Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer

AU - Che, Meixia

AU - Chaturvedi, Aashi

AU - Munro, Sarah A.

AU - Pitzen, Samuel P.

AU - Ling, Alex

AU - Zhang, Weijie

AU - Mentzer, Josh

AU - Ku, Sheng Yu

AU - Puca, Loredana

AU - Zhu, Yanyun

AU - Bergman, Andries M.

AU - Severson, Tesa M.

AU - Forster, Colleen

AU - Liu, Yuzhen

AU - Hildebrand, Jacob

AU - Daniel, Mark

AU - Wang, Ting You

AU - Selth, Luke A.

AU - Hickey, Theresa

AU - Zoubeidi, Amina

AU - Gleave, Martin

AU - Bareja, Rohan

AU - Sboner, Andrea

AU - Tilley, Wayne

AU - Carroll, Jason S.

AU - Tan, Winston

AU - Kohli, Manish

AU - Yang, Rendong

AU - Hsieh, Andrew C.

AU - Murugan, Paari

AU - Zwart, Wilbert

AU - Beltran, Himisha

AU - Huang, R. Stephanie

AU - Dehm, Scott M.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85118616251&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-26612-1

DO - 10.1038/s41467-021-26612-1

M3 - Article

C2 - 34737261

AN - SCOPUS:85118616251

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 6377

ER -

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

Abstract

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