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Link to original content: https://pubmed.ncbi.nlm.nih.gov/33485843
RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis - PubMed Skip to main page content
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. 2021 Mar 1;400(1):112493.
doi: 10.1016/j.yexcr.2021.112493. Epub 2021 Jan 22.

RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis

Kehan Ren  1 , Danmei Zhou  1 , Meili Wang  2 , Ermin Li  3 , Chenjian Hou  1 , Ying Su  1 , Qiang Zou  4 , Ping Zhou  3 , Xiuping Liu  5
Affiliations

RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis

Kehan Ren et al. Exp Cell Res. .

Abstract

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-1a, a key mitochondrial biogenesis regulator, presumably by the increased mitophagy intensity induced by RACGAP1. PGC-1a 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-1a 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.

Keywords: Breast cancer; Mitochondrial dynamics; Mitochondrial quality control; RACGAP1; Tumor metastasis.

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