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Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells

Cheng, Chun-Ting and Kuo, Ching-Ying and Ouyang, Ching and Li, Chien-Feng and Chung, Yiyin and Chan, David C. and Kung, Hsing-Jien and Ann, David K. (2016) Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells. Cancer Research, 76 (17). pp. 5006-5018. ISSN 0008-5472. PMCID PMC5316485. https://resolver.caltech.edu/CaltechAUTHORS:20160914-080907190

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/0008-5472.CAN-15-2921DOIArticle
http://cancerres.aacrjournals.org/content/76/17/5006PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316485/PubMed CentralArticle
ORCID:
AuthorORCID
Chan, David C.0000-0002-0191-2154
Additional Information:© 2016 American Association for Cancer Research. Received October 20, 2015; revised May 26, 2016; accepted June 15, 2016; published Online First June 30, 2016. No potential conflicts of interest were disclosed. Authors' Contributions: Conception and design: C.-T. Cheng, C.-Y. Kuo, C.-F. Li, D.K. Ann Development of methodology: C.-T. Cheng, C.-Y. Kuo, Y. Chung, D.K. Ann Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.-T. Cheng, C.-Y. Kuo, C. Ouyang, C.-F. Li, Y. Chung Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C.-T. Cheng, C.-Y. Kuo, C. Ouyang, C.-F. Li, D.C. Chan, H.-J. Kung, D.K. Ann Writing, review, and/or revision of the manuscript: C.-T. Cheng, C.-Y. Kuo, C. Ouyang, D.C. Chan, H.-J. Kung, D.K. Ann Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.-T. Cheng, C. Ouyang, D.K. Ann Study supervision: C.-T. Cheng, D.K. Ann This study was financially supported by National Institute of Health Research Grants R01DE10742, R01DE14183, and The Mary Kay Foundation Research Grant number 005-13 (D.K. Ann), Ministry of Health and Welfare Research Grant MOHW103-TD-M-111-102001 (C.-F. Li), R01CA165263, R01CA150197, MOHW104-TDU-M-212-13304, MOST102-2320-B-400-018-MY3, MOST104-2321-B-400-009, NHRI05A1-MGPP15-014 (H.-J. Kung), and P30CA33572. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. We are sincerely grateful to Drs. Emily Wang and Art Riggs for their helpful suggestions and critical reading of manuscript, Ms. Lucy Brown of the Analytical Cytometry Core for flow cytometry analyses, Dr. Brian Armstrong and Ms. Tina Patel of the Light Microscopy Core for microscopy analyses, Mr. Austin Changou for processing time lapse imaging analyses, Drs. Xiwei Wu and Jinhui Wang and Mr. Charles Warden of Functional Genomics Core for RNA-seq data analyses, Ms. Tina Montgomery and Ms. Sofia Loera of Pathology Core for immunohistochemical analyses, Dr. Tzu-Ju Chen for pathological evaluation, Drs. Marcia Miller, Zhuo Li, and Ricardo Zerda of Electron Microscopy Core and Mr. Kevin Chi for EM image analysis and members of Dr. Ann's laboratory for helpful discussions and Dr. Nancy Linford for editing.
Funders:
Funding AgencyGrant Number
NIHR01DE10742
NIHR01DE14183
Mary Kay Foundation005-13
Ministry of Health and Welfare (Taipei)MOHW103-TD-M-111-102001
NIHR01CA165263
NIHR01CA150197
Ministry of Health and Welfare (Taipei)MOHW104-TDU-M-212-13304
Ministry of Science and Technology (Taipei)MOST102-2320-B-400-018-MY3
Ministry of Science and Technology (Taipei)MOST104-2321-B-400-009
NIHNHRI05A1-MGPP15-014
National Cancer InstituteP30CA33572
Issue or Number:17
PubMed Central ID:PMC5316485
Record Number:CaltechAUTHORS:20160914-080907190
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160914-080907190
Official Citation: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 and David K. Ann Cancer Res September 1 2016 (76) (17) 5006-5018; DOI: 10.1158/0008-5472.CAN-15-2921
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70330
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 Sep 2016 18:17
Last Modified:24 Feb 2020 10:30

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