DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling.
DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling.
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作者：
Chan DW;Hui WW;Wang JJ;Yung MM;Hui LM;Qin Y;Liang RR;Leung TH;Xu D;Chan KK;Yao KM;Tsang BK;Ngan HY
最近来自全面基因组分析和功能研究的证据表明，FOXM 1是驱动癌症进展的关键转移调节因子。然而，FOXM 1在癌细胞中发挥其转移功能的调节机制仍然不清楚。在这里，我们报告DLX 1作为FOXM 1下游靶点，在卵巢癌中发挥促转移功能。两种FOXM 1亚型（FOXM 1B或FOXM 1C）都可以通过两个保守的结合位点转录上调DLX 1，分别位于DLX 1启动子下游+61至+69 bp（TFBS 1）和上游-675至-667 bp（TFBS 2）。在高级别浆液性卵巢癌中，FOXM 1和DLX 1的核表达之间的显著相关性进一步加强了这种调节。在功能上，DLX 1的异位表达促进了小鼠卵巢癌细胞的生长、细胞迁移/侵袭和卵巢癌的腹膜内扩散，而小干扰RNA介导的FOXM 1过表达卵巢癌细胞中DLX 1的敲低废除了这些致癌能力。相比之下，通过shRNAi去除FOXM 1仅部分减弱肿瘤生长，并且对细胞迁移/侵袭和DLX 1过表达卵巢癌细胞的腹膜内扩散几乎没有影响。此外，机制研究表明，DLX 1通过在TGF-β1诱导后与细胞核中的SMAD 4直接相互作用上调派-1和JUNB来正向调节转化生长因子-β（TGF-β）信号传导。总之，这些数据强烈表明DLX 1在FOXM 1信号传导中具有关键作用，通过增强高级别浆液性卵巢癌细胞中的TGF-β/SMAD 4信号传导来促进癌症侵袭性。
Recent evidence from a comprehensive genome analysis and functional studies have revealed that FOXM1 is a crucial metastatic regulator that drives cancer progression. However, the regulatory mechanism by which FOXM1 exerts its metastatic functions in cancer cells remains obscure. Here, we report that DLX1 acts as a FOXM1 downstream target, exerting pro-metastatic function in ovarian cancers. Both FOXM1 isoforms (FOXM1B or FOXM1C) could transcriptionally upregulate DLX1 through two conserved binding sites, located at +61 to +69bp downstream (TFBS1) and −675 to −667bp upstream (TFBS2) of the DLX1 promoter, respectively. This regulation was further accentuated by the significant correlation between the nuclear expression of FOXM1 and DLX1 in high-grade serous ovarian cancers. Functionally, the ectopic expression of DLX1 promoted ovarian cancer cell growth, cell migration/invasion and intraperitoneal dissemination of ovarian cancer in mice, whereas small interfering RNA-mediated DLX1 knockdown in FOXM1-overexpressing ovarian cancer cells abrogated these oncogenic capacities. In contrast, depletion of FOXM1 by shRNAi only partially attenuated tumor growth and exerted almost no effect on cell migration/invasion and the intraperitoneal dissemination of DLX1-overexpressing ovarian cancer cells. Furthermore, the mechanistic studies showed that DLX1 positively modulates transforming growth factor-β (TGF-β) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-β1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-β/SMAD4 signaling in high-grade serous ovarian cancer cells.