Estrogen-related receptor alpha directly binds to p53 and cooperatively controls colon cancer growth through the regulat
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RESEARCH
Open Access
Estrogen-related receptor alpha directly binds to p53 and cooperatively controls colon cancer growth through the regulation of mitochondrial biogenesis and function Humberto De Vitto1, Joohyun Ryu1, Ali Calderon-Aparicio1, Josh Monts1, Raja Dey1, Abhijit Chakraborty1, Mee-Hyun Lee2, Ann M. Bode1* and Zigang Dong2*
Abstract Background: Of the genes that control mitochondrial biogenesis and function, ERRα emerges as a druggable metabolic target to be exploited for cancer therapy. Of the genes mutated in cancer, TP53 remains the most elusive to target. A clear understanding of how mitochondrial druggable targets can be accessed to exploit the underlying mechanism(s) explaining how p53-deficient tumors promote cell survival remains elusive. Methods: We performed protein-protein interaction studies to demonstrate that ERRα binds to p53. Moreover, we used gene silencing and pharmacological approaches in tandem with quantitative proteomics analysis by SWATHMS to investigate the role of the ERRα/p53 complex in mitochondrial biogenesis and function in colon cancer. Finally, we designed in vitro and in vivo studies to investigate the possibility of targeting colon cancers that exhibit defects in p53. Results: Here, we are the first to identify a direct protein-protein interaction between the ligand-binding domain (LBD) of ERRα and the C-terminal domain (CTD) of p53. ERRα binds to p53 regardless of p53 mutational status. Furthermore, we show that the ERRα and p53 complex cooperatively control mitochondrial biogenesis and function. Targeting ERRα creates mitochondrial metabolic stresses, such as production of reactive oxygen species (ROS) and mitochondrial membrane permeabilization (MMP), leading to a greater cytotoxic effect that is dependent on the presence of p53. Pharmacological inhibition of ERRα impairs the growth of p53-deficient cells and of p53 mutant patient-derived colon xenografts (PDX). Conclusions: Therefore, our data suggest that by using the status of the p53 protein as a selection criterion, the ERRα/p53 transcriptional axis can be exploited as a metabolic vulnerability. Keywords: ERRα, p53-deficient, Mitochondrial biogenesis, Mitochondrial oxidative phosphorylation (mtOxPhos), PDX colon cancer model, Apoptosis
* Correspondence: [email protected]; [email protected] 1 The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin 55912, USA 2 Department of Pathophysiology, Zhengzhou University School of Medicine, 40 North Road, 27 District University, Zhengzhou 450052, China © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated
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