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

• Published in: Nature communications Vol. 10; no. 1; pp. 1034 - 17
• Main Authors: Ma, Biao, Cheng, Hongcheng, Mu, Chenglong, Geng, Guangfeng, Zhao, Tian, Luo, Qian, Ma, Kaili, Chang, Rui, Liu, Qiangqiang, Gao, Ruize, Nie, Junli, Xie, Jiaying, Han, Jinxue, Chen, Linbo, Ma, Gui, Zhu, Yushan, Chen, Quan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 631/67/2329; 631/67/327; 631/80/642/333; 631/80/86; Acidosis; Animals; Apoptosis; Apoptosis - drug effects; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Cancer; Cell death; Cell Death - drug effects; Cell Line, Tumor; Cellular Reprogramming; Clustered Regularly Interspaced Short Palindromic Repeats - genetics; Degradation; Disease Models, Animal; Environmental effects; FADD protein; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Heterogeneity; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia - metabolism; Immune response; Immune system; Lysine; Macrophages; Macrophages - drug effects; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microenvironments; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; multidisciplinary; Necrosis; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Respiratory Factor 1 - genetics; Nuclear Respiratory Factor 1 - metabolism; Polarization; Pyruvic acid; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Tumor cells; Tumor Microenvironment; Tumors; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08618-y

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. Tumor cell-microenvironment interactions generate heterogeneity and promote progression. Here, Ma et al. show that the E3 ligase SIAH2 degrades NRF1 in response to hypoxia to enhance pro-tumor metabolic and environmental effects, whereas NRF1 stabilization sensitizes tumor cells to apoptosis.