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

TitleOpposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsChe M, Chaturvedi A, Munro SA, Pitzen SP, Ling A, Zhang W, Mentzer J, Ku S-Y, Puca L, Zhu Y, Bergman AM, Severson TM, Forster C, Liu Y, Hildebrand J, Daniel M, Wang T-Y, 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, R Huang S, Dehm SM
JournalNat Commun
Volume12
Issue1
Pagination6377
Date Published2021 Nov 04
ISSN2041-1723
KeywordsCell Line, Tumor, Humans, Kruppel-Like Transcription Factors, Male, Neoplasm Staging, Neuroendocrine Cells, Prostatic Neoplasms, Castration-Resistant, Receptor, ErbB-2, Receptors, Androgen, Signal Transduction, Transcriptional Activation
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.

DOI10.1038/s41467-021-26612-1
Alternate JournalNat Commun
PubMed ID34737261
PubMed Central IDPMC8568894
Grant ListR01 CA229618 / CA / NCI NIH HHS / United States
R01 CA204856 / CA / NCI NIH HHS / United States
R01 CA174777 / CA / NCI NIH HHS / United States
R37 CA241486 / CA / NCI NIH HHS / United States
R01 CA212097 / CA / NCI NIH HHS / United States
R37 CA230617 / CA / NCI NIH HHS / United States
Related Faculty: 
Andrea Sboner, Ph.D.

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