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

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.

SUBMITTER: Ma JB

PROVIDER: S-EPMC7297795 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Ma Jian-Bin JB Bai Ji-Yu JY Zhang Hai-Bao HB Jia Jing J Shi Qi Q Yang Chao C Wang Xinyang X He Dalin D Guo Peng P

Cell death & disease 20200616 6

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; moreo ...[more]

PMID: 32546700

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Project description:BackgroundCastration-resistant prostate cancer often metastasizes to the bone, and such bone metastases eventually become resistant to available therapies, leading to the death of patients. Enriched in the bone, TGF-β plays a pivotal role in bone metastasis development. However, directly targeting TGF-β or its receptors has been challenging for the treatment of bone metastasis. We previously found that TGF-β induces and then depends on the acetylation of transcription factor KLF5 at K369 to regulate multiple biological processes, including the induction of EMT, cellular invasiveness, and bone metastasis. Acetylated KLF5 (Ac-KLF5) and its downstream effectors are thus potential therapeutic targets for treating TGF-β-induced bone metastasis in prostate cancer.MethodsA spheroid invasion assay was applied to prostate cancer cells expressing KLF5K369Q, which mimics Ac-KLF5, to screen 1987 FDA-approved drugs for invasion suppression. Luciferase- and KLF5K369Q-expressing cells were injected into nude mice via the tail artery to model bone metastasis. Bioluminescence imaging, micro-CT), and histological analyses were applied to monitor and evaluate bone metastases. RNA-sequencing, bioinformatic, and biochemical analyses were used to understand nitazoxanide (NTZ)-regulated genes, signaling pathways, and the underlying mechanisms. The binding of NTZ to KLF5 proteins was evaluated using fluorescence titration, high-performance liquid chromatography (HPLC), and circular dichroism (CD) analysis.ResultsNTZ, an anthelmintic agent, was identified as a potent invasion inhibitor in the screening and validation assays. In KLF5K369Q-induced bone metastasis, NTZ exerted a potent inhibitory effect in preventive and therapeutic modes. NTZ also inhibited osteoclast differentiation, a cellular process responsible for bone metastasis induced by KLF5K369Q. NTZ attenuated the function of KLF5K369Q in 127 genes' upregulation and 114 genes' downregulation. Some genes' expression changes were significantly associated with worse overall survival in patients with prostate cancer. One such change was the upregulation of MYBL2, which functionally promotes bone metastasis in prostate cancer. Additional analyses demonstrated that NTZ bound to the KLF5 protein, KLF5K369Q bound to the promoter of MYBL2 to activate its transcription, and NTZ attenuated the binding of KLF5K369Q to the MYBL2 promoter.ConclusionsNTZ is a potential therapeutic agent for bone metastasis induced by the TGF-β/Ac-KLF5 signaling axis in prostate cancer and likely other cancers.

Dataset Information

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

Publications

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

Similar Datasets

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