PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition

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

doi:10.3390/cancers13081772

PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition

Cancers (Basel). 2021 Apr 8;13(8):1772. doi: 10.3390/cancers13081772.

Authors

Taek-In Oh^{1

2}, Mingyu Lee^{3

4

5}, Yoon-Mi Lee¹, Geon-Hee Kim^{1

2}, Daekee Lee⁶, Jueng Soo You⁷, Sun Ha Kim⁸, Minyoung Choi⁸, Hyonchol Jang⁸, Yeong-Min Park⁹, Hyun-Woo Shin^{3

4

5}, Dong Hoon Shin⁸, Ji-Hong Lim^{1

2

10}

Affiliations

¹ Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Korea.
² Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea.
³ Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul 03080, Korea.
⁴ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
⁵ Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
⁶ Department of Life Science, Ewha Womans University, Seoul 03760, Korea.
⁷ Department of Biochemistry, School of Medicine, Konkuk University, Seoul 05029, Korea.
⁸ Research Institute, National Cancer Center, Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea.
⁹ Department of Immunology, School of Medicine, Konkuk University, Seoul 05029, Korea.
¹⁰ Diabetes and Bio-Research Center, Konkuk University, Chungju 27478, Korea.

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.

Keywords: EMT; ID1; PGC1α; TCF4; TWIST1; lung cancer; metastasis.