[HTML][HTML] The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
B Ma, H Cheng, C Mu, G Geng, T Zhao, Q Luo… - Nature …, 2019 - nature.com
B Ma, H Cheng, C Mu, G Geng, T Zhao, Q Luo, K Ma, R Chang, Q Liu, R Gao, J Nie, J Xie…
Nature communications, 2019•nature.comThe 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 …
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 …
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.
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