KLF5 inhibits STAT3 activity and tumor metastasis in prostate cancer by suppressing IGF1 transcription cooperatively with HDAC1

Jian-Bin Ma,Jing Jia,Chao Yang,Ji-Yu Bai,Xinyang Wang,Hai-Bao Zhang,Qi Shi,Peng Guo,Dalin He

doi:10.1038/s41419-020-2671-1

Abstract

KLF5 is frequently deleted and downregulated in prostate cancer, and recently it has been reported that KLF5 loss is enriched in the aggressive branches of prostate cancer evolution. However, why KLF5 loss is associated with prostate cancer aggressiveness is still not clear. Herein, we analyzed KLF5 expression in TCGA and GEO database, as well as prostate cancer tissue microarray, and found that KLF5 expression significantly decreased in prostate cancer accompanying with tumor progression; moreover, KLF5 downregulation was associated with shorter survival of patients. Interestingly, we also found that KLF5 expression was obviously lower in prostate cancer metastases than in localized tissues, indicating that KLF5 downregulation is associated with prostate cancer invasion and metastasis. To assess this effect of KLF5, we knocked down KLF5 in prostate cancer cells and found that KLF5 knockdown promoted invasive ability of prostate cancer cells in vitro and in vivo. Moreover, we found that KLF5 downregulation enhanced the expression of IGF1 and STAT3 phosphorylation, while block of IGF1 with antibody decreased the enhancement of STAT3 activity and prostate cancer cell invasive ability by KLF5 knockdown, indicating that KLF5 inhibits prostate cancer invasion through suppressing IGF1/STAT3 pathway. Mechanistically, we found that KLF5 interacted with deacetylase HDAC1 and KLF5 is necessary for the binding of HDAC1 on IGF1 promoter to suppress IGF1 transcription. Taken together, our results indicate that KLF5 could be an important suppressor of prostate cancer invasion and metastasis, because KLF5 could suppress the transcription of IGF1, a tumor cell autocrine cytokine, and its downstream cell signaling to inhibit cell invasive ability, and reveal a novel mechanism for STAT3 activation in prostate cancer. These findings may provide evidence for the precision medicine in prostate cancer.

Highlights

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related mortality in males in the USA1
Expression of KLF5 is decreased during prostate cancer progression, and its downregulation is associated with shorter survival of patients
Consistent with the KLF5 protein expression pattern in Fig. 1a, we found that KLF5 mRNA expression decreased in high Gleason score 8–10 PCa tissues compared with low Gleason score 6–7 tissues (Fig. 1d, e)

Summary

Introduction

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related mortality in males in the USA1. Krüpple-like transcription factor 5 (KLF5/IKLF/ BTEB2), which is a zinc-finger transcription factor, has various functions in different cellular processes, including proliferation, apoptosis, invasion, and differentiation[4,5]. Official journal of the Cell Death Differentiation Association. Ma et al Cell Death and Disease (2020)11:466 transcription factors and epigenetic enzymes, such as ERβ, SMAD4, p300, and HDAC3, into the transcriptional complex to activate or repress the target gene transcription[6,7,8]. Conditional Klf[5] deletion in mouse prostate epithelial cells promoted Pten deletion and initiated tumorigenesis[11], further suggesting that KLF5 may function as a tumor suppressor in PCa. the association between KLF5 expression and the clinical features of PCa, and whether KLF5 regulates the invasiveness of PCa cells remain to be elucidated

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Results

Conclusion