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

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.

Identification of Key MicroRNAs and Mechanisms in Prostate Cancer Evolution Based on Biomarker Prioritization Model and Carcinogenic Survey

“…Li et al showed that KLF5 was a key factor in androgen- AR signaling. It promoted the proliferation of PCa cells and could serve as a therapeutic target for PCa treatment (Li et al, 2020 ). As a famous star driving the carcinogenesis of PCa from normal prostate tissue to cancer biology, the AR signaling has already been explored across different researches, and the results in this study computationally demonstrated new insights and improved the understandings in AR -mediated PCa genesis.…”

Characterization of DNA Methylation and Screening of Epigenetic Markers in Polycystic Ovary Syndrome

“…Some of the genes such as ETS1 and FGFR1 have been reported to participate in the development of PCOS ( Song et al, 2019 ; Patil et al, 2020 ). Among the other genes, KLF5 is an important transcription factor that regulates androgen-AR signaling ( Li et al, 2020 ); CYP1B1, a dioxin-inducible oxidoreductase, is involved in the metabolism of estradiol ( Muneeb et al, 2014 ); IRS1 is an insulin receptor substrate gene that mediates the control of various cellular processes by insulin ( Kasch et al, 2018 ; Park et al, 2018 ). These genes were significantly enriched in biological processes of adipocyte differentiation, insulin resistance, female pregnancy, and circadian rhythm, indicating they are likely to be involved in pathogenesis of PCOS.…”

Post-Translational Modifications That Drive Prostate Cancer Progression

“…The transcription factors Krüppel-like factor 5 and 6 (KLF5 and KLF6) are critically involved in prostate cancer progression [ 386 , 387 ]. Recently, it was shown that KLF5 acetylation regulates luminal differentiation of basal progenitors in prostate development and regeneration [ 388 ] and is involved in TGFβ caused docetaxel resistance [ 389 ].…”