PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition

SIMPLE SUMMARY: Despite the therapeutic advances, lung cancer is the most dangerous cancer with poor 5-year survival rate due to metastasis and recurrence. Accumulated evidence indicates that the epithelial–mesenchymal transition (EMT) is considered to be responsible for the lung cancer metastasis; however, the transcriptional frameworks that regulate EMT-related gene expression are still poorly understood. Here, we suggest that cooperation of TCF4-TWIST1 controlled by the PGC1α-ID1 transcriptional axis mediates EMT and lung cancer metastasis, and that this molecular framework is an attractive target for lung cancer diagnosis and treatment. ABSTRACT: PGC1α oppositely regulates cancer metastasis in melanoma, breast, and pancreatic cancer; however, little is known about its impact on lung cancer metastasis. Transcriptome and in vivo xenograft analysis show that a decreased PGC1α correlates with the epithelial–mesenchymal transition (EMT) and lung cancer metastasis. The deletion of a single Pgc1α allele in mice promotes bone metastasis of Kras(G12D)-driven lung cancer. Mechanistically, PGC1α predominantly activates ID1 expression, which interferes with TCF4-TWIST1 cooperation during EMT. Bioinformatic and clinical studies have shown that PGC1α and ID1 are downregulated in lung cancer, and correlate with a poor survival rate. Our study indicates that TCF4-TWIST1-mediated EMT, which is regulated by the PGC1α-ID1 transcriptional axis, is a potential diagnostic and therapeutic target for metastatic lung cancer.