Metabolic stress-induced phosphorylation of kap1 ser473 blocks mitochondrial fusion in breast cancer cells

Chun Ting Cheng, Ching Ying Kuo, Ching Ouyang, Chien Feng Li, Yiyin Chung, David C. Chan, Hsing Jien Kung, David K. Ann

研究成果: 雜誌貢獻文章

20 引文 斯高帕斯(Scopus)

摘要

Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROSand p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473- KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose- starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress.
原文英語
頁(從 - 到)5006-5018
頁數13
期刊Cancer Research
76
發行號17
DOIs
出版狀態已發佈 - 九月 1 2016
對外發佈Yes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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