Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Korea.
Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 380-701, Korea.
Int J Mol Sci. 2022 Jul 26;23(15):8247. doi: 10.3390/ijms23158247.
The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a critical transcriptional coactivator that maintains metabolic homeostasis and energy expenditure by cooperating with various transcription factors. Recent studies have shown that PGC1α deficiency promotes lung cancer metastasis to the bone through activation of TCF4 and TWIST1-mediated epithelial-mesenchymal transition (EMT), which is suppressed by the inhibitor of DNA binding 1 (ID1); however, it is not clear which transcription factor participates in PGC1α-mediated EMT and lung cancer metastasis. Here, we identified forkhead box A1 (FOXA1) as a potential transcription factor that coordinates with PGC1α and ID1 for EMT gene expression using transcriptome analysis. Cooperation between FOXA1 and PGC1α inhibits promoter occupancy of TCF4 and TWIST1 on CDH1 and CDH2 proximal promoter regions due to increased ID1, consequently regulating the expression of EMT-related genes such as CDH1, CDH2, VIM, and PTHLH. Transforming growth factor beta 1 (TGFβ1), a major EMT-promoting factor, was found to decrease ID1 due to the suppression of FOXA1 and PGC1α. In addition, ectopic expression of ID1, FOXA1, and PGC1α reversed TGFβ1-induced EMT gene expression. Our findings suggest that FOXA1- and PGC1α-mediated ID1 expression involves EMT by suppressing TCF4 and TWIST1 in response to TGFβ1. Taken together, this transcriptional framework is a promising molecular target for the development of therapeutic strategies for lung cancer metastasis.
过氧化物酶体增殖物激活受体 γ 共激活因子 1-α（PGC1α）是一种关键的转录共激活因子，通过与各种转录因子合作，维持代谢稳态和能量消耗。最近的研究表明，PGC1α 缺乏通过激活 TCF4 和 TWIST1 介导的上皮-间充质转化（EMT）促进肺癌向骨骼转移，而 DNA 结合抑制因子 1（ID1）抑制了这种转移；然而，尚不清楚哪种转录因子参与了 PGC1α 介导的 EMT 和肺癌转移。在这里，我们通过转录组分析鉴定出叉头框蛋白 A1（FOXA1）是一种潜在的转录因子，它与 PGC1α 和 ID1 共同协调 EMT 基因的表达。FOXA1 和 PGC1α 的合作由于 ID1 的增加而抑制了 TCF4 和 TWIST1 在 CDH1 和 CDH2 近端启动子区域的启动子占据，从而调节 EMT 相关基因如 CDH1、CDH2、VIM 和 PTHLH 的表达。转化生长因子 β1（TGFβ1）是一种主要的 EMT 促进因子，由于 FOXA1 和 PGC1α 的抑制，发现 TGFβ1 降低了 ID1。此外，ID1、FOXA1 和 PGC1α 的异位表达逆转了 TGFβ1 诱导的 EMT 基因表达。我们的研究结果表明，FOXA1 和 PGC1α 介导的 ID1 表达通过 TGFβ1 抑制 FOXA1 和 PGC1α 来抑制 TCF4 和 TWIST1，从而涉及 EMT。总之，这个转录框架是开发肺癌转移治疗策略的有前途的分子靶点。
