The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment.
The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment.
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DOI：
10.18632/oncotarget.12525
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发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Carbone GM
中科院分区：
文献类型：
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作者：
Albino D;Civenni G;Rossi S;Mitra A;Catapano CV;Carbone GM
转移性前列腺癌是一个尚未解决的临床问题，由于高频率的复发和治疗阻力。了解导致前列腺癌进展的途径是预防这种致命疾病的重要任务。ETS转录因子ESE 3/EHF在人前列腺上皮细胞分化中具有重要作用。前列腺上皮细胞中ESE 3/EHF的缺失决定了转化、上皮向间质转化（EMT）和获得干细胞样特性。在这项研究中，我们确定IL-6作为ESE 3/EHF的直接靶点，在ESE 3/EHF丧失后在前列腺上皮细胞中被激活。前列腺肿瘤中ESE 3/EHF与IL-6呈显著负相关。染色质免疫沉淀证实了ESE 3/EHF与IL-6基因启动子中新的ETS结合位点的结合。致瘤性ESE 3/EHF敲低前列腺上皮细胞模型中IL-6逆转转化和干细胞样表型的抑制相反，IL-6刺激诱导恶性表型，干细胞样行为和STAT 3激活。与粘附的大量癌细胞相比，在前列腺球中观察到IL-6水平增加，这与STAT 3的更强活化相关。IL-6升高和ESE 3/EHF缺失的人前列腺肿瘤与STAT 3激活相关，并显示与细胞粘附、癌干细胞样和转移扩散相关的基因上调。JAK抑制剂对IL-6/STAT 3激活的药理学抑制在体外抑制了癌症干细胞生长并在体内抑制了自我更新。这项研究确定了转录因子ESE 3/EHF和IL-6/JAK/STAT 3通路之间的新联系，并表明靶向该轴可能优先有益于ESE 3/EHF缺失的肿瘤。
Metastatic prostate cancer represents a yet unsolved clinical problem due to the high frequency of relapse and treatment resistance. Understanding the pathways that lead to prostate cancer progression is an important task to prevent this deadly disease. The ETS transcription factor ESE3/EHF has an important role in differentiation of human prostate epithelial cells. Loss of ESE3/EHF in prostate epithelial cells determines transformation, epithelial-to-mesenchymal transition (EMT) and acquisition of stem-like properties. In this study we identify IL-6 as a direct target of ESE3/EHF that is activated in prostate epithelial cells upon loss of ESE3/EHF. ESE3/EHF and IL-6 were significantly inversely correlated in prostate tumors. Chromatin immunoprecipitation confirmed binding of ESE3/EHF to a novel ETS binding site in the IL-6 gene promoter. Inhibition of IL-6 reverted transformation and stem-like phenotype in tumorigenic ESE3/EHF knockdown prostate epithelial cell models. Conversely, IL-6 stimulation induced malignant phenotypes, stem-like behavior and STAT3 activation. Increased level of IL-6 was observed in prostatospheres compared with adherent bulk cancer cells and this was associated with stronger activation of STAT3. Human prostate tumors with IL-6 elevation and loss of ESE3/EHF were associated with STAT3 activation and displayed upregulation of genes related to cell adhesion, cancer stem-like and metastatic spread. Pharmacological inhibition of IL-6/STAT3 activation by a JAK inhibitor restrained cancer stem cell growth in vitro and inhibited self-renewal in vivo. This study identifies a novel connection between the transcription factor ESE3/EHF and the IL-6/JAK/STAT3 pathway and suggests that targeting this axis might be preferentially beneficial in tumors with loss of ESE3/EHF.