JQ1 promotes invasion in a BET protein independent manner in prostate cancer. JQ1 promotes invasion in a BET protein independent manner in prostate cancer

Recent findings have shown that inhibitors targeting BET (bromodomain and extraterminal domain) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports also have revealed that JQ1 can activate additional oncogenic pathways and may affect EMT (epithelial mesenchymal transition). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein independent manner. Multiple invasion pathways including EMT, BMP (bone morphogenetic protein) signaling, chemokine signaling and focal adhesion pathway were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of FOXA1, an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1, inactivated FOXA1 binding to its interacting repressors, TLE3, HDAC7 and NFIC, thus blocking FOXA1 repressive function and activating the invasion genes. Our finding indicates that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents could not be ignored during cancer treatment, especially in FOXA1 related cancers. Overall design: mRNA profiles of LNCaP cells treated with JQ1 for 3 days with or without BRD4 knockdown. RNA-sequencing and analysis was performed by EA | Q² Solutions, Morrisville, NC 27560.

最新研究表明，靶向BET蛋白（bromodomain and extraterminal domain）的抑制剂（如小分子JQ1）对多种肿瘤细胞具有强效增殖抑制活性，在癌症治疗中具备潜在应用价值。然而，部分研究亦显示JQ1可激活额外的致癌信号通路，且可能影响上皮间质转化（epithelial mesenchymal transition）。因此，探究JQ1治疗潜在的非预期效应（如细胞侵袭与转移）具有重要的科学意义。本研究显示，在前列腺癌中，JQ1可抑制肿瘤细胞增殖，但以不依赖BET蛋白的方式促进细胞侵袭与转移。JQ1可激活包括上皮间质转化、骨形态发生蛋白（bone morphogenetic protein）信号通路、趋化因子信号通路及黏着斑通路在内的多条侵袭相关通路，进而促进肿瘤细胞侵袭。值得注意的是，JQ1通过抑制前列腺癌中的侵袭抑制因子叉头框A1（FOXA1），诱导侵袭相关基因的上调表达。JQ1可直接与FOXA1结合，阻断FOXA1与其相互作用的抑制因子TLE3、HDAC7及NFIC的结合，从而抵消FOXA1的转录抑制功能并激活侵袭相关基因的表达。本研究结果表明，JQ1在前列腺癌中存在促进细胞侵袭的非预期效应。因此，在癌症治疗过程中，JQ1及其衍生治疗药物的不良效应不容忽视，尤其在FOXA1相关肿瘤中。整体实验设计：对经JQ1处理3天的LNCaP细胞（存在或不存在BRD4敲低）进行mRNA表达谱检测。RNA测序及数据分析由EA | Q² Solutions公司（美国北卡罗来纳州莫里斯维尔，邮编27560）完成。