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.

KLF5在前列腺癌中经常被删除和下调，最近有报道说KLF5的缺失在前列腺癌进化的侵袭性分支中富集。但是，为什么KLF5丢失与前列腺癌的侵袭性相关仍不清楚。在本文中，我们分析了TCGA和GEO数据库以及前列腺癌组织芯片中的KLF5表达，发现伴随肿瘤进展的前列腺癌中KLF5表达显着降低。此外，KLF5下调与患者生存期缩短有关。有趣的是，我们还发现前列腺癌转移中的KLF5表达明显低于局部组织，这表明KLF5下调与前列腺癌的侵袭和转移有关。为了评估KLF5的这种效果，我们敲低了前列腺癌细胞中的KLF5，发现KLF5敲低促进了前列腺癌细胞在体外和体内的侵袭能力。此外，我们发现KLF5的下调增强了IGF1的表达和STAT3的磷酸化，而用抗体阻断IGF1则通过KLF5的抑制降低了STAT3活性和前列腺癌细胞侵袭能力的增强，表明KLF5通过抑制IGF1 / STAT3抑制了前列腺癌的侵袭。途径。从机理上讲，我们发现KLF5与脱乙酰基酶HDAC1相互作用，而KLF5对于结合HDAC1 而用抗体阻断IGF1则通过KLF5敲低降低了STAT3活性和前列腺癌细胞侵袭能力的增强，表明KLF5通过抑制IGF1 / STAT3途径抑制了前列腺癌的侵袭。从机理上讲，我们发现KLF5与脱乙酰基酶HDAC1相互作用，而KLF5对于结合HDAC1 而用抗体阻断IGF1则通过KLF5敲低降低了STAT3活性和前列腺癌细胞侵袭能力的增强，表明KLF5通过抑制IGF1 / STAT3途径抑制了前列腺癌的侵袭。从机理上讲，我们发现KLF5与脱乙酰基酶HDAC1相互作用，而KLF5对于结合HDAC1IGF1启动子可抑制IGF1转录。两者合计，我们的结果表明KLF5可能是前列腺癌侵袭和转移的重要抑制因子，因为KLF5可以抑制IGF1的转录，一种肿瘤细胞自分泌细胞因子及其下游细胞信号传导，从而抑制细胞侵袭能力，并揭示出一种新的STAT3激活在前列腺癌中的作用机制。这些发现可能为前列腺癌的精确医学提供证据。