PGC1α Cooperates with FOXA1 to Regulate Epithelial Mesenchymal Transition through the TCF4-TWIST1

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 canc...

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Published in:International journal of molecular sciences 2022-08, Vol.23 (15), p.8247
Main Authors: Fang, Xue-Quan, Lee, Mingyu, Lim, Woo-Jin, Lee, Seonghoon, Lim, Chang-Hoon, Lim, Ji-Hong
Format: Article
Language:English
Subjects:
Binding sites
Bone cancer
Cooperation
E-cadherin
Ectopic expression
EMT gene
Energy expenditure
Enzymes
Estrogens
Forkhead protein
Gene expression
Growth factors
Homeostasis
Id1 protein
Liver
Lung cancer
Melanoma
Mesenchyme
Metabolism
Metastases
Metastasis
Prostate cancer
Proteins
Skin cancer
Transcription factors
Transcriptomes
Transforming growth factor-b1
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23158247