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

Research output: Contribution to journalArticlepeer-review

2 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 languageEnglish (US)
Article number6377
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
L.P. is an employee of Loxo Oncology at Lilly, this work was completed prior to her employment at Loxo, she is acting on her own, and these endeavors are not in an manner affiliated with Loxo Oncology at Lilly. H.B. has received research funding from Janssen, Abbvie Stemcentryx, Astellas, Eli Lilly, Millenium and has served as advisor/consultant for Janssen, Astellas, Amgen, Astra Zeneca, Pfizer, Sanofi Genzyme. A.C.H. has received research funding from eFFECTOR Therapeutics. S.M.D. is principal investigator on grants to University of Minnesota from Astellas/Pfizer and Janssen. S.M.D. has served as advisor/ consultant for Celgene/Bristol Myers Squibb, Janssen, and Oncternal Therapeutics.

Funding Information:
We are grateful to Dr. Yu Chen (Memorial Sloan Kettering Cancer Center) for providing MSK-PCA3 organoids. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results. The authors acknowledge support from the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for lab support and the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support. This work was supported by NIH grants R01CA174777 (to S.M.D.), R01CA212097 (to M.K.), R37CA230617 (to A.C.H.), R01CA204856 and R01CA229618 (to R.S.H.), R37CA241486 (to H.B.), Prostate Cancer Foundation Challenge Awards (to S.M.D., M.G., A.Z., and H.B.), the DOD PCRP (W81XWH-19-1-0161 to RY and W81XWH-17-1-0653 to H.B.), National Health and Medical Research Council of Australia (ID 1121057 to L.A.S. and W.T.), a research grant from the Avon Foundation for Women (to R.S.H), and a University of Minnesota Faculty Research Development Grant (to S.M.D. and R.S.H.). L.A.S. is supported by a Principal Cancer Research Fellowship awarded by Cancer Council’s Beat Cancer project on behalf of its donors, the State Government through the Department of Health and the Australian Government through the Medical Research Future Fund. This research received immunohistochemistry assistance from the University of Minnesota’s Biorepository and Laboratory Services program and was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences grant L1TUR002494. Funding was received from Astellas for H3K27ac analysis with clinical specimens.

Publisher Copyright:
© 2021, The Author(s).

PubMed: MeSH publication types

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

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