Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression

Abstract

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77’s inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.

Oxidative stress impairs the Nur77-SIRT1 axis resulting in a decline in organism homeostasis during aging

“…The orphan nuclear receptor, Nur77 (also called TR3), shares common regulatory signaling pathways with SIRT1, including metabolic homeostasis, ROS removal and in ammatory response decline 19,[22][23][24] .…”

“…We conclude that the downregulation of Nur77 in aged tissues may be associated with biological functions of organ aging and cellular senescence. Early functional studies have pointed to the critical role of Nur77 in negatively regulating the production of several senescence-associated secretory factors, including reactive oxygen, TNF-α, IL-1β and fatty acid 19,[22][23][24] . In this study, deletion of Nur77 resulted in shortened lifespan, ROS accumulation and the elevation of the senescent marker, β-galactosidase, in multiple tissues.…”

PPARγ Mediates the Anti-Epithelial-Mesenchymal Transition Effects of FGF1ΔHBS in Chronic Kidney Diseases via Inhibition of TGF-β1/SMAD3 Signaling

“…In addition to transcriptional activity, PPARγ binds to other proteins and regulates their function. Yang et al (2020) found that decreased interaction between PPARγ and Nur77 resulted in enhanced stability of Nur77 and inhibited metabolic reprogramming in breast cancer. Interactions between PPARγ and NLRP3, β-arrestin-1, and UBR5 regulated inflammatory responses of macrophages, adipogenesis, and endothelial homeostasis ( Zhuang et al, 2011 ; Li et al, 2019 ; Yang et al, 2021 ).…”

How cancer cells remodel lipid metabolism: strategies targeting transcription factors

“…Nur77 recruits PPARγ to the CD36 promoter and FABP4 to suppress transcription of these genes, thus preventing FA uptake and cell proliferation. PPARγ physically binds to Nur77 and facilitates ubiquitin ligase Trim13-mediated ubiquitination of Nur77, thereby aggravating breast cancer [ 93 ].…”