PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition

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 KrasG12D-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.

Polygonum cuspidatum Extract (Pc-Ex) Containing Emodin Suppresses Lung Cancer-Induced Cachexia by Suppressing TCF4/TWIST1 Complex-Induced PTHrP Expression

“…Previous studies have reported that the TGFβ1 signalling pathway promotes the interaction between TCF4 and TWIST1 and consequently upregulates the expression of EMT-related genes [ 16 ]. The interaction between TCF4 and TWIST1 was also confirmed in this study ( Figure 2 A).…”

“…PTHLH, which is encoded by parathyroid hormone-related protein (PTHrP), serves as an external stimulus to maintain bone turnover and skeletal homeostasis [ 14 ]. Previous studies have reported that PTHrP promotes the growth, metastasis, and chemoresistance of various cancers, such as lung, colorectal, prostate, pancreatic, and breast cancers [ 15 , 16 , 17 , 18 , 19 , 20 ]. A recent study reported that tumour-derived PTHrP causes cancer cachexia by promoting WAT browning and skeletal muscle loss [ 4 ].…”

“…The E-protein TCF4 (also called E2-2 and ITF2), which is a class I basic helix-loop-helix (bHLH) transcription factor, is involved in the pathogenesis of Fuchs’ endothelial corneal dystrophy, primary sclerosing cholangitis, Pitt–Hopkins syndrome, and several types of malignant tumours [ 21 ]. TCF4 exerts oncogenic effects by promoting the proliferation, invasion, and chemoresistance of melanoma, lung, colorectal, and breast cancers [ 16 , 22 , 23 , 24 , 25 , 26 ]. In contrast, several studies have demonstrated that TCF4 suppresses the growth and progression, which are associated with poor prognosis, of non-small cell lung carcinoma and colorectal cancer [ 27 , 28 , 29 , 30 ].…”

“…TWIST1 undergoes homodimerization or heterodimerization with various E-proteins, including TCF3, TCF4, and TCF12 [ 32 ]. Additionally, TCF4 interacts with TWIST1, promotes EMT and TGFβ1 signalling, and subsequently enhances bone metastasis in Kras G12V -driven lung cancer [ 16 ]. The mechanisms underlying the interaction between TCF4 and TWIST1 and the role of the TCF4–TWIST1 complex in cancer cachexia have not been investigated.…”

Statins Decrease Programmed Death-Ligand 1 (PD-L1) by Inhibiting AKT and β-Catenin Signaling

“…To analyze the gene expression, quantitative PCR was performed using the SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA, USA) and LightCycler96 real-time PCR (Roche, Basel, Switzerland). Ct values were normalized to the human 36B4 gene and relative mRNA expression was calculated versus human 36B4 expression as previously described [ 36 ]. The primer sequences used in the experiment are shown in Table 1 .…”