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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5006-5018
Number of pages13
JournalCancer Research
Volume76
Issue number17
DOIs
Publication statusPublished - Sep 1 2016
Externally publishedYes

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Mitochondrial Dynamics
Physiological Stress
Phosphorylation
Breast Neoplasms
Starvation
Glucose
Neoplasms
Mitochondria
Down-Regulation
Molecular Imaging
Oxidative Phosphorylation
Heterografts
Cell Survival
Proteins
Food

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cheng, C. T., Kuo, C. Y., Ouyang, C., Li, C. F., Chung, Y., Chan, D. C., ... Ann, D. K. (2016). Metabolic stress-induced phosphorylation of kap1 ser473 blocks mitochondrial fusion in breast cancer cells. Cancer Research, 76(17), 5006-5018. https://doi.org/10.1158/0008-5472.CAN-15-2921

Metabolic stress-induced phosphorylation of kap1 ser473 blocks mitochondrial fusion in breast cancer cells. / Cheng, Chun Ting; Kuo, Ching Ying; Ouyang, Ching; Li, Chien Feng; Chung, Yiyin; Chan, David C.; Kung, Hsing Jien; Ann, David K.

In: Cancer Research, Vol. 76, No. 17, 01.09.2016, p. 5006-5018.

Research output: Contribution to journalArticle

Cheng, Chun Ting ; Kuo, Ching Ying ; Ouyang, Ching ; Li, Chien Feng ; Chung, Yiyin ; Chan, David C. ; Kung, Hsing Jien ; Ann, David K. / Metabolic stress-induced phosphorylation of kap1 ser473 blocks mitochondrial fusion in breast cancer cells. In: Cancer Research. 2016 ; Vol. 76, No. 17. pp. 5006-5018.
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