RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis
RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis
复制标题
RACGAP1 调节 ECT2 依赖性线粒体质量控制以驱动乳腺癌转移
DOI：
10.1016/j.yexcr.2021.112493
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发表时间：
2021-02-16
影响因子：
3.7
通讯作者：
Liu, Xiuping
中科院分区：
文献类型：
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作者：
Ren, Kehan;Zhou, Danmei;Liu, Xiuping
大多数癌症死亡是由于肿瘤细胞在远处器官中的定植。越来越多的证据表明RACGAP 1的过表达在肿瘤转移中起着关键作用。然而，对潜在的机制仍然知之甚少。我们发现RACGAP 1通过调节线粒体质量控制促进乳腺癌转移。RACGAP 1在乳腺癌细胞中的过表达导致线粒体断裂，线粒体自噬强度增加，线粒体周转和有氧糖酵解ATP产生。我们发现RACGAP 1在分裂后期通过募集ECT 2促进线粒体分裂，随后激活ERK-DRP 1通路。我们进一步证明了RACGAP 1的磷酸化对于其与ECT 2结合的能力及其下游效应是必不可少的。RACGAP 1过表达也增加了PGC-1 α的表达，PGC-1 α是一种关键的线粒体生物发生调节因子，推测是通过RACGAP 1诱导的线粒体自噬强度增加。PGC-1a增加了线粒体中DNMT 1的富集，线粒体DNMT 1增强了线粒体DNA甲基化并上调了线粒体基因组转录。我们的数据表明，RACGAP 1通过调节DRP 1磷酸化和PGC-1 α表达，同时促进线粒体自噬和线粒体生物合成，最终改善乳腺癌细胞线粒体质量控制。我们的研究为理解RACGAP 1过表达与乳腺癌相关的恶性肿瘤提供了一个新的角度。
Most cancer deaths are due to the colonization of tumor cells in distant organs. More evidence indicates that overexpression of RACGAP1 plays a critical role in cancer metastasis. However, the underlying mechanism still remains poorly understood. Here we found that RACGAP1 promoted breast cancer metastasis through regulating mitochondrial quality control. Overexpression of RACGAP1 in breast cancer cells led to the fragmentation of mitochondria, increased mitophagy intensity, mitochondrial turnover, and aerobic glycolysis ATP production. We showed that RACGAP1 promoted mitochondrial fission through recruiting ECT2 during anaphase and subsequently had activated ERK-DRP1 pathway. We further demonstrated the phosphorylation of RACGAP1 is essential for its ability of binding with ECT2 and its downstream effects. RACGAP1 overexpression also increased the expression of PGC-1 a, a key mitochondrial biogenesis regulator, presumably by the increased mitophagy intensity induced by RACGAP1. PGC-1 a increased the enrichment of DNMT1 in mitochondria, mitochondrial DNMT1 augmented mitochondrial DNA methylation and upregulated mitochondrial genome transcription. Our data indicated that RACGAP1 simultaneously facilitated mitophagy and mitochondrial biogenesis through regulating DRP1 phosphorylation and PGC-1 a expression, eventually improved mitochondrial quality control in breast cancer cells. Our study provided a new angle in understanding the RACGAP1-overexpression related malignancy in breast cancer patients.