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.
Highlights
The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression
We identified that Fas-associated protein with death domain (FADD), which encodes a core component of death-inducing signaling complex (DISC) during apoptosis, is a NRF1 target gene and its expression is reduced in response to hypoxia
Using large-scale gene transcription profiling data from the Gene Expression Omnibus (GEO) database, we identified that breast tumors had significantly reduced transcription of genes enriched in gene sets: precursor metabolites generation, fatty acid oxidation, and energy derivation through oxidation (Fig. 1a)
Summary
The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. 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 impairs the polarization of TAMs, and 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. These results reveal a series of intrinsic and extrinsic cellular reactions during tumor progression and demonstrate the importance of these processes in tumor maintenance
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