Title | Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Che 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 |
Journal | Nat Commun |
Volume | 12 |
Issue | 1 |
Pagination | 6377 |
Date Published | 2021 Nov 04 |
ISSN | 2041-1723 |
Keywords | Cell 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. |
DOI | 10.1038/s41467-021-26612-1 |
Alternate Journal | Nat Commun |
PubMed ID | 34737261 |
PubMed Central ID | PMC8568894 |
Grant List | R01 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.