PGC1α Loss Promotes Lung Cancer Metastasis Through Epithelial-Mesenchymal Transition

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Apr 30

PMID 33917757

Citations 12

Authors

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

Affiliations

Soon will be listed here.

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-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.

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References

Perk J, Iavarone A, Benezra R . Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer. 2005; 5(8):603-14. DOI: 10.1038/nrc1673. View

Ligresti G, Caporarello N, Meridew J, Jones D, Tan Q, Choi K . CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis. JCI Insight. 2019; 5. PMC: 6629126. DOI: 10.1172/jci.insight.127111. View

Cruz-Bermudez A, Vicente-Blanco R, Laza-Briviesca R, Garcia-Grande A, Laine-Menendez S, Gutierrez L . PGC-1alpha levels correlate with survival in patients with stage III NSCLC and may define a new biomarker to metabolism-targeted therapy. Sci Rep. 2017; 7(1):16661. PMC: 5709355. DOI: 10.1038/s41598-017-17009-6. View

Mologni L, Dekhil H, Ceccon M, Purgante S, Lan C, Cleris L . Colorectal tumors are effectively eradicated by combined inhibition of {beta}-catenin, KRAS, and the oncogenic transcription factor ITF2. Cancer Res. 2010; 70(18):7253-63. DOI: 10.1158/0008-5472.CAN-10-1108. View

Kaminski L, Torrino S, Dufies M, Djabari Z, Haider R, Roustan F . PGC1α Inhibits Polyamine Synthesis to Suppress Prostate Cancer Aggressiveness. Cancer Res. 2019; 79(13):3268-3280. PMC: 7293888. DOI: 10.1158/0008-5472.CAN-18-2043. View

Doran A, Meller N, Cutchins A, Deliri H, Slayton R, Oldham S . The helix-loop-helix factors Id3 and E47 are novel regulators of adiponectin. Circ Res. 2008; 103(6):624-34. PMC: 2746666. DOI: 10.1161/CIRCRESAHA.108.175893. View

Puisieux A, Brabletz T, Caramel J . Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014; 16(6):488-94. DOI: 10.1038/ncb2976. View

Kim Y, Lee Y, Oh T, Shin D, Kim G, Kan S . Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism. Int J Mol Sci. 2018; 19(10). PMC: 6213641. DOI: 10.3390/ijms19103127. View

LeBleu V, OConnell J, Gonzalez Herrera K, Wikman H, Pantel K, Haigis M . PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014; 16(10):992-1003, 1-15. PMC: 4369153. DOI: 10.1038/ncb3039. View

10.

Vicent S, Luis-Ravelo D, Anton I, Garcia-Tunon I, Borras-Cuesta F, Dotor J . A novel lung cancer signature mediates metastatic bone colonization by a dual mechanism. Cancer Res. 2008; 68(7):2275-85. DOI: 10.1158/0008-5472.CAN-07-6493. View

11.

Veerasamy M, Phanish M, Dockrell M . Smad mediated regulation of inhibitor of DNA binding 2 and its role in phenotypic maintenance of human renal proximal tubule epithelial cells. PLoS One. 2013; 8(1):e51842. PMC: 3540025. DOI: 10.1371/journal.pone.0051842. View

12.

Tsai J, Yang J . Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013; 27(20):2192-206. PMC: 3814640. DOI: 10.1101/gad.225334.113. View

13.

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

14.

Roschger C, Cabrele C . The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal. 2017; 15(1):7. PMC: 5267474. DOI: 10.1186/s12964-016-0161-y. View

15.

Bhalla K, Hwang B, Dewi R, Ou L, Twaddel W, Fang H . PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis. Cancer Res. 2011; 71(21):6888-98. PMC: 3282487. DOI: 10.1158/0008-5472.CAN-11-1011. View

16.

Chaffer C, San Juan B, Lim E, Weinberg R . EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016; 35(4):645-654. DOI: 10.1007/s10555-016-9648-7. View

17.

Patil M, Sharma B, Elattar S, Chang J, Kapil S, Yuan J . Id1 Promotes Obesity by Suppressing Brown Adipose Thermogenesis and White Adipose Browning. Diabetes. 2017; 66(6):1611-1625. PMC: 5440025. DOI: 10.2337/db16-1079. View

18.

Zhang M, Clawson G, Olivieri N, BELL L, Begley C, Miller B . Expression of SCL is normal in transfusion-dependent Diamond-Blackfan anemia but other bHLH proteins are deficient. Blood. 1997; 90(5):2068-74. View

19.

Kamalian L, Gosney J, Forootan S, Foster C, Bao Z, Beesley C . Increased expression of Id family proteins in small cell lung cancer and its prognostic significance. Clin Cancer Res. 2008; 14(8):2318-25. DOI: 10.1158/1078-0432.CCR-07-4716. View

20.

DAntonio C, Passaro A, Gori B, Del Signore E, Migliorino M, Ricciardi S . Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies. Ther Adv Med Oncol. 2014; 6(3):101-14. PMC: 3987652. DOI: 10.1177/1758834014521110. View