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 language | English |
|---|---|
| Pages (from-to) | 5006-5018 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - Sep 1 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
T1 - Metabolic stress-induced phosphorylation of kap1 ser473 blocks mitochondrial fusion in breast cancer cells
AU - Cheng, Chun Ting
AU - Kuo, Ching Ying
AU - Ouyang, Ching
AU - Li, Chien Feng
AU - Chung, Yiyin
AU - Chan, David C.
AU - Kung, Hsing Jien
AU - Ann, David K.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84986904946&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84986904946&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-2921
DO - 10.1158/0008-5472.CAN-15-2921
M3 - Article
C2 - 27364555
AN - SCOPUS:84986904946
VL - 76
SP - 5006
EP - 5018
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 17
ER -