PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition.

Taek-In Oh,Minyoung Choi,Hyonchol Jang,Sun Ha Kim,Jueng Soo You,Dong Hoon Shin,Geon-Hee Kim,Ji-Hong Lim,Yeong-Min Park,Mingyu Lee,Hyun-Woo Shin,Daekee Lee,Yoon-Mi Lee

doi:10.3390/cancers13081772

Abstract

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 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.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.

Highlights

Lung cancer is the most common type of cancer to metastasize to the bones
Because PGC1α levels in A549 cells were much higher than other lung cancer cell lines, we analyzed the transcriptome to investigate the functional role of altered PGC1α expression in A549 lung cancer cells
PGC1α and ID1 expression positively correlated with the expression of E-cadherin, the representative epithelial marker (Figure 5G). These results suggest that the expression of PGC1α and ID1 was downregulated in lung cancers, with an expression pattern reminiscent of a high metastatic potential and a poor clinical outcome

Summary

Introduction

Lung cancer is the most common type of cancer to metastasize to the bones. Secondary bone tumors are often observed in approximately 30–40% of lung cancer patients during the course of their disease [1]. The epithelial–mesenchymal transition (EMT) is required for activating invasiveness and metastasis, which is considered a hallmark of cancer in most solid tumors of the epithelial origin: Lung, colorectal, breast, prostate, and pancreatic cancer [2,3]. Multiple types of transcription factors, such as TWIST1, SNAIL, SLUG, ZEB1, and ZEB2, are required for EMT [4]. TWIST1 was originally identified as a basic helix–loop–helix (bHLH) transcription factor that determines cell fate during embryonic development and morphogenesis [5,6]

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