FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer.
FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer.
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DOI：
10.1016/j.celrep.2015.09.063
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发表时间：
2015-11-03
期刊：
影响因子：
8.8
通讯作者：
Cui X
中科院分区：
文献类型：
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作者：
Han B;Qu Y;Jin Y;Yu Y;Deng N;Wawrowsky K;Zhang X;Li N;Bose S;Wang Q;Sakkiah S;Abrol R;Jensen TW;Berman BP;Tanaka H;Johnson J;Gao B;Hao J;Liu Z;Buttyan R;Ray PS;Hung MC;Giuliano AE;Cui X
中胚层和上皮-间质转化相关转录因子FOXC 1在基底细胞样乳腺癌（BLBC）中特异性过表达，但其生化功能尚不清楚。在这里，我们证明了FOXC 1通过激活Smoothened（SMO）非依赖性Hedgehog（Hh）信号传导控制BLBC细胞中富集的癌症干细胞（CSC）特性。Hh的这种非典型激活是由Gli 2特异性介导的。我们进一步表明，FOXC 1的N-末端结构域（aa 1-68）直接结合到Gli 2的内部区域（aa 898-1168），增强Gli 2的DNA结合和转录激活能力。FOXC 1表达与Gli 2及其靶点在人乳腺癌中的表达相关。此外，FOXC 1过表达降低BLBC细胞和异种移植肿瘤对抗Hedgehog（Hh）抑制剂的敏感性。总之，这些发现揭示了FOXC 1介导的非经典Hh信号传导，其决定了BLBC干细胞样表型和抗Hh敏感性，支持抑制FOXC 1通路作为改善BLBC治疗的潜在方法。
The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. We further show that the N-terminal domain of FOXC1 (aa 1–68) binds directly to an internal region (aa 898–1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.