The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression

Biao Ma (), Hongcheng Cheng, Chenglong Mu, Guangfeng Geng, Tian Zhao, Qian Luo, Kaili Ma, Rui Chang, Qiangqiang Liu, Ruize Gao, Junli Nie, Jiaying Xie, Jinxue Han, Linbo Chen, Gui Ma, Yushan Zhu () and Quan Chen ()
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Biao Ma: Nankai University
Hongcheng Cheng: Nankai University
Chenglong Mu: Nankai University
Guangfeng Geng: Nankai University
Tian Zhao: Nankai University
Qian Luo: Nankai University
Kaili Ma: Nankai University
Rui Chang: Nankai University
Qiangqiang Liu: Nankai University
Ruize Gao: Nankai University
Junli Nie: Nankai University
Jiaying Xie: Nankai University
Jinxue Han: Nankai University
Linbo Chen: Nankai University
Gui Ma: Nankai University
Yushan Zhu: Nankai University
Quan Chen: Nankai University

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer.

Date: 2019
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DOI: 10.1038/s41467-019-08618-y

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