Pgc1 Alpha Loss Promotes Lung Cancer Metastasis Through Epithelial-Mesenchymal Transition

Simple SummaryDespite 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 PGC1 alpha-ID1 transcriptional axis mediates EMT and lung cancer metastasis, and that this molecular framework is an attractive target for lung cancer diagnosis and treatment.PGC1 alpha 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 PGC1 alpha correlates with the epithelial-mesenchymal transition (EMT) and lung cancer metastasis. The deletion of a single Pgc1 alpha allele in mice promotes bone metastasis of Kras(G12D)-driven lung cancer. Mechanistically, PGC1 alpha predominantly activates ID1 expression, which interferes with TCF4-TWIST1 cooperation during EMT. Bioinformatic and clinical studies have shown that PGC1 alpha 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 PGC1 alpha-ID1 transcriptional axis, is a potential diagnostic and therapeutic target for metastatic lung cancer.