Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). 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, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.

中文翻译：

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小分子JQ1通过BET独立的FOXA1失活促进前列腺癌的侵袭。

最近的发现表明，靶向溴结构域和末端外域（BET）蛋白的抑制剂，例如小分子JQ1，是许多癌症的有效生长抑制剂，并有望用于癌症治疗。但是，一些报道也显示JQ1可以激活其他致癌途径，并可能影响上皮到间充质转化（EMT）。因此，重要的是要解决JQ1治疗的潜在意外效应，例如细胞侵袭和转移。在这里，我们表明，在前列腺癌中，JQ1以BET蛋白非依赖性的方式抑制癌细胞的生长，但促进其侵袭和转移。JQ1激活了包括EMT，骨形态发生蛋白（BMP）信号传导，趋化因子信号传导和黏着斑粘附在内的多种入侵途径，以促进入侵。值得注意的是 JQ1通过抑制叉头盒蛋白A1（FOXA1）（一种前列腺癌的入侵抑制因子）诱导了入侵基因的上调。JQ1直接与FOXA1相互作用，并使FOXA1与其相互作用的阻遏物TLE3，HDAC7和NFIC结合失活，从而阻断FOXA1的阻遏功能并激活入侵基因。我们的发现表明，JQ1具有促进前列腺癌浸润的出乎意料的作用。因此，在癌症治疗期间，尤其是在FOXA1相关的癌症中，不能忽略JQ1或其衍生治疗剂的不良作用。从而阻断FOXA1的抑制功能并激活入侵基因。我们的发现表明，JQ1具有促进前列腺癌浸润的出乎意料的作用。因此，在癌症治疗期间，尤其是在FOXA1相关的癌症中，不能忽略JQ1或其衍生治疗剂的不良作用。从而阻断FOXA1的抑制功能并激活入侵基因。我们的发现表明，JQ1具有促进前列腺癌浸润的出乎意料的作用。因此，在癌症治疗期间，尤其是在FOXA1相关的癌症中，不能忽略JQ1或其衍生治疗剂的不良作用。