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

**Juan Li 1,2, Baotong Zhang 3, Mingcheng Liu 1,2, Xing Fu 1,2, Xinpei Ci 4, Jun A 1,2, Changying Fu 1,2, Ge Dong 1, Rui Wu 1,2, Zhiqian Zhang 2, Liya Fu <sup>1</sup> and Jin-Tang Dong 2,3,\***


Received: 26 February 2020; Accepted: 17 March 2020; Published: 21 March 2020

**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.

**Keywords:** KLF5; androgen receptor; cell proliferation; tumorigenesis; prostate cancer
