title: Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells.
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 ROS- and 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. Cancer Res; 76(17); 5006-18. ©2016 AACR.
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, California.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Cheng
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, California.
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Ching
authors.initials: C
authors.lastname: Ouyang
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, California.
authors.forename: Yiyin
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Department of Biology and Biological Engineering, California Institute of Technology, Pasadena, California.
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
authors.affiliation: Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, California. National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, California. dann@coh.org.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D019295:Computational Biology; D005260:Female; D005455:Fluorescent Antibody Technique; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D063154:Mitochondrial Dynamics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D024101:Mitochondrial Proteins; D012097:Repressor Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human