The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
2019
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-
NRF1axis remodels
tumor microenvironmentthrough 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
SIAH2spatially 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
NRF1degradation 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
NRF1degradation is a potential therapeutic strategy against cancer.
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