The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
复制标题
SIAH2-NRF1轴在空间上调节肿瘤微环境重塑以促进肿瘤进展
DOI：
10.1038/s41467-019-08618-y
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发表时间：
2019-03-04
影响因子：
16.6
通讯作者：
Chen, Quan
中科院分区：
文献类型：
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作者：
Ma, Biao;Cheng, Hongcheng;Chen, Quan
肿瘤细胞与其微环境（包括缺氧、酸中毒和免疫细胞）之间的相互作用导致肿瘤异质性，从而促进肿瘤进展。在这里，我们发现SIAH2-NRF1轴通过调节肿瘤线粒体功能、肿瘤相关巨噬细胞（TAM）极化和细胞死亡来重塑肿瘤微环境，从而促进肿瘤的维持和进展。从机制上讲，乳腺癌中线粒体基因表达低与临床结果不佳有关。缺氧激活的 E3 连接酶 SIAH2 在空间上下调核编码的线粒体基因表达，包括丙酮酸脱氢酶 beta，通过赖氨酸 230 泛素化来降解 NRF1（核呼吸因子 1），从而增强 Warburg 效应、代谢重编程和促肿瘤免疫反应。抑制缺氧下 NRF1 的降解不仅会损害 TAM 的极化，还会促使肿瘤细胞更容易以 FADD 依赖性方式发生凋亡，从而因胞吞作用受损而导致继发性坏死。这些数据表明抑制 NRF1 降解是一种潜在的癌症治疗策略。
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 includingpyruvate dehydrogenase betavia 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.