Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression
Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression
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DOI：
10.1172/jci122367
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发表时间：
2019-02-01
影响因子：
15.9
通讯作者：
Yu, Jindan
中科院分区：
文献类型：
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作者：
Song, Bing;Park, Su-Hong;Yu, Jindan
前列腺癌（PC）发展为去势抵抗（CRPC）是一种致命疾病。CRPC肿瘤通过谱系可塑性对新一代抗雄激素enzalutamide产生耐药性，谱系可塑性以上皮-间质转化（EMT）和基底样表型为特征。FOXA1是上皮谱系分化所必需的转录因子。在这里，我们证明FOXA1的缺失导致转化生长因子β 3 （TGFB3）的显著上调，TGFB3编码tgf - β途径的配体。从机制上讲，这是由于FOXA1在TGFB3基因的上游增强子上占据，直接抑制其转录。功能上，FOXA1下调可诱导tgf - β信号转导、EMT和细胞运动，这些可被tgf - β受体I抑制剂galunisertib （LY2157299）有效阻断。组织微阵列分析证实，与原发肿瘤相比，CRPC中FOXA1蛋白水平降低，tgf - β信号传导水平一致升高（SMAD2磷酸化表明）。重要的是，LY2157299联合治疗使PC细胞对恩杂鲁胺敏感，从而在体外抑制细胞侵袭和体内抑制异种移植CRPC肿瘤生长和转移方面产生协同作用。因此，我们的研究确定FOXA1是部分由tgf - β信号介导的谱系可塑性的重要调节因子，并支持一种新的治疗策略来控制谱系转换，并可能延长抗雄激素治疗的临床反应。
Prostate cancer (PC) progressed to castration resistance (CRPC) is a fatal disease. CRPC tumors develop resistance to new-generation antiandrogen enzalutamide through lineage plasticity, characterized by epithelial-mesenchymal transition (EMT) and a basal-like phenotype. FOXA1 is a transcription factor essential for epithelial lineage differentiation. Here, we demonstrate that FOXA1 loss leads to remarkable upregulation of transforming growth factor beta 3 (TGFB3), which encodes a ligand of the TGF-beta pathway. Mechanistically, this is due to genomic occupancy of FOXA1 on an upstream enhancer of the TGFB3 gene to directly inhibit its transcription. Functionally, FOXA1 downregulation induces TGF-beta signaling, EMT, and cell motility, which is effectively blocked by the TGF-beta receptor I inhibitor galunisertib (LY2157299). Tissue microarray analysis confirmed reduced levels of FOXA1 protein and a concordant increase in TGF-beta signaling, indicated by SMAD2 phosphorylation, in CRPC as compared with primary tumors. Importantly, combinatorial LY2157299 treatment sensitized PC cells to enzalutamide, leading to synergistic effects in inhibiting cell invasion in vitro and xenograft CRPC tumor growth and metastasis in vivo. Therefore, our study establishes FOXA1 as an important regulator of lineage plasticity mediated in part by TGF-beta signaling, and supports a novel therapeutic strategy to control lineage switching and potentially extend clinical response to antiandrogen therapies.