KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

• Type of Material: Article
• Authors: Juan Li, Nankai University; Baotong Zhang, Emory University; Mingcheng Liu, Nankai University; Xing Fu, Nankai University; Xinpei Ci, University of British Columbia; A Jun, Nankai University; Changying Fu, Nankai University; Ge Dong, Nankai University; Rui Wu, Nankai University; Zhang Zhiqian, Southern University of Science and Technology; Liya Fu, Nankai University; Jin-Tang Dong, Emory University
• Language: English
• Date: 2020-03-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers12030748
• Title of Journal or Parent Work: Cancers
• Volume: 12
• Issue: 3
• Grant/Funding Information: This research received no external funding.
• Keywords: Abiraterone; Receptor; KLF5; PTEN; Resistance; Kruppel-like factor 5; Suppresses; Oncology; Transcription; Life Sciences & Biomedicine; cell proliferation; tumorigenesis; Enzalutamide; Science & Technology; Expression; androgen receptor; prostate cancer; Inhibition
• Research Categories: Health Sciences, Oncology; Biology, Genetics; Biology, Cell

Abstract

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.