**1. Introduction**

Prostate cancer (PCa) is prevalent among older men; and is one of the common causes of cancer-related death in men. While genetic and epigenetic alterations of multiple genes, including loss of *PTEN* [1–3], fusion between *TMPRSS2* and *ERG* [4,5], amplification and over-expression of *MYC*, and inactivation of *P53* and *RB* [3], initiate and promote prostatic carcinogenesis [6–8], androgen/androgen receptor (AR) signaling is the driving force in the process [9,10]. AR is thus a major therapeutic target, and androgen deprivation therapy (ADT) via surgical or chemical castration, including abiraterone and enzalutamide treatment, is thus the most commonly used effective therapy for patients with PCa. Unfortunately, PCa often develop resistance to ADT and become castration-resistant prostate cancers (CRPCs), which usually maintain AR activity by different mechanisms, such as

generating AR splice variants, gain-of-function mutations in *AR*, and functional alterations leading to androgen independence [11–13].

AR is a member of the nuclear steroid receptor superfamily that is predominantly activated by testosterone and di-hydrotestosterone [14,15]. AR signaling is essential not only for postnatal development and maintenance of normal prostates but also for the regeneration of prostates after androgen deprivation. AR signaling also promotes the development and progression of PCa via enhanced cell proliferation and survival [16]. Many PCa driver genes alter the activity or structure of AR or are regulated by AR signaling during prostatic carcinogenesis.

KLF5 is a basic transcription factor that belongs to the Krüppel-like factor (KLF) family. It regulates a variety of biological processes including cell proliferation, apoptosis, angiogenesis, stemness and the epithelial-mesenchymal transition (EMT) [17,18]. KLF5 also functions in multiple pro- and anti-proliferative signaling pathways, including the RAS/ERK and PI3K/AKT proliferative pathways and the TGF-β anti-proliferative signaling to regulate different cancer cell behaviors [19–21]. As a transcription factor, KLF5 interacts with other transcription factors such as c-Jun [22], p53 [23], and ERα [24] to regulate the transcription of many genes involved in cell proliferation and tumorigenesis [25], including *CCND1* and *MYC* [26–28]. In the prostate, KLF5 also plays crucial roles in postnatal development, regeneration after castration, and PCa. In both human and mouse prostates, Klf5 is expressed in both basal and luminal cells, and basal cells preferentially express acetylated Klf5 [29,30]. Androgen ablation by castration in mice increases both Klf5 expression level and the number of KLF5-expressing cells [29], and both Klf5 and acetylated Klf5 are indispensable for the maintenance of basal progenitors and their luminal differentiation [30]. Klf5 and its acetylation are also necessary for the survival and regeneration of basal progenitor-derived luminal cells following castration and subsequent androgen restoration [30]. During tumorigenesis, the deletion of *Klf5* promotes *Pten* loss-induced prostate tumors, and the *Klf5*-/- /*Pten*-/- tumors also have increased basal to luminal differentiation [31].

Taken together with the facts that androgen/AR signaling is the driving force in both normal prostate development and regeneration and PCa development, both KLF5 and AR are transcription factors, and androgen appears to induce the expression of *KLF5* in PCa cells [32,33], we propose that KLF5 and AR could be functionally associated with each other in prostatic carcinogenesis. We tested this hypothesis in this study. We demonstrated that silencing *KLF5* inhibited cell proliferation and tumor growth of PCa cells. In addition, as a transcription factor, KLF5 occupied the promoter of *AR* to promote its transcription; and KLF5 was also required for AR's transcriptional activity. Furthermore, KLF5 and AR interacted with each other to regulate transcription of AR target genes (e.g., *MYC*, *CCND1,* and *PSA*) to promote cell proliferation and tumor growth. These findings suggest that specific targeting of the AR-KLF5 interaction could be a potential therapeutic strategy for disrupting androgen signaling in PCa treatment.
