Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer
Abstract Background Cyclin C (CCNC) was reported to take part in regulating mitochondria‐derived oxidative stress under cisplatin stimulation. However, its effect in gastric cancer is unknown. This study aimed to investigate the role of cyclin C and its ubiquitylation in regulating cisplatin resista...
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| Format: | Article |
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Wiley
2022-03-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.770 |
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| author | Hong‐yue Jiang Ying‐ling Chen Xing‐xing Xu Chuan‐yin Li Yun Chen Dong‐ping Li Xiao‐qing Zeng Hong Gao |
| author_facet | Hong‐yue Jiang Ying‐ling Chen Xing‐xing Xu Chuan‐yin Li Yun Chen Dong‐ping Li Xiao‐qing Zeng Hong Gao |
| author_sort | Hong‐yue Jiang |
| collection | DOAJ |
| description | Abstract Background Cyclin C (CCNC) was reported to take part in regulating mitochondria‐derived oxidative stress under cisplatin stimulation. However, its effect in gastric cancer is unknown. This study aimed to investigate the role of cyclin C and its ubiquitylation in regulating cisplatin resistance in gastric cancer. Methods The interaction between HECT domain and ankyrin repeat‐containing E3 ubiquitin‐protein ligase 1 (HACE1) and cyclin C was investigated by GST pull‐down assay, co‐immunoprecipitation and ubiquitylation assay. Mitochondria‐derived oxidative stress was studied by MitoSOX Red assay, seahorse assay and mitochondrial membrane potential measurement. Cyclin C‐associated cisplatin resistance was studied in vivo via xenograft. Results HACE1 catalysed the ubiquitylation of cyclin C by adding Lys11‐linked ubiquitin chains when cyclin C translocates to cytoplasm induced by cisplatin treatment. The ubiquitin‐modified cyclin C then anchor at mitochondira, which induced mitochondrial fission and ROS synthesis. Depleting CCNC or mutation on the ubiquitylation sites decreased mitochondrial ROS production and reduced cell apoptosis under cisplatin treatment. Xenograft study showed that disrupting cyclin C ubiquitylation by HACE1 conferred impairing cell apoptosis response upon cisplatin administration. Conclusions Cyclin C is a newly identified substrate of HACE1 E3 ligase. HACE1‐mediated ubiquitylation of cyclin C sheds light on a better understanding of cisplatin‐associated resistance in gastric cancer patients. Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer. With cisplatin‐induced nuclear–mitochondrial translocation of cyclin C, its ubiquitylation by HACE1 increased mitochondrial fission and mitochondrial‐derived oxidative stress, leading to cell apoptosis. |
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| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-13T15:47:13Z |
| publishDate | 2022-03-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-20093a6ce93b4fb584081677d92da7872022-12-22T02:40:56ZengWileyClinical and Translational Medicine2001-13262022-03-01123n/an/a10.1002/ctm2.770Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancerHong‐yue Jiang0Ying‐ling Chen1Xing‐xing Xu2Chuan‐yin Li3Yun Chen4Dong‐ping Li5Xiao‐qing Zeng6Hong Gao7Department of Gastroenterology and Hepatology Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Gastroenterology and Hepatology Zhongshan Hospital Fudan University Shanghai ChinaState Key Laboratory of Molecular Biology CAS Center for Excellence in Molecular Cell Science Innovation Center for Cell Signaling Network Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences Shanghai ChinaState Key Laboratory of Molecular Biology CAS Center for Excellence in Molecular Cell Science Innovation Center for Cell Signaling Network Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences Shanghai ChinaDepartment of Gastroenterology and Hepatology Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Gastroenterology and Hepatology Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Gastroenterology and Hepatology Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Gastroenterology and Hepatology Zhongshan Hospital Fudan University Shanghai ChinaAbstract Background Cyclin C (CCNC) was reported to take part in regulating mitochondria‐derived oxidative stress under cisplatin stimulation. However, its effect in gastric cancer is unknown. This study aimed to investigate the role of cyclin C and its ubiquitylation in regulating cisplatin resistance in gastric cancer. Methods The interaction between HECT domain and ankyrin repeat‐containing E3 ubiquitin‐protein ligase 1 (HACE1) and cyclin C was investigated by GST pull‐down assay, co‐immunoprecipitation and ubiquitylation assay. Mitochondria‐derived oxidative stress was studied by MitoSOX Red assay, seahorse assay and mitochondrial membrane potential measurement. Cyclin C‐associated cisplatin resistance was studied in vivo via xenograft. Results HACE1 catalysed the ubiquitylation of cyclin C by adding Lys11‐linked ubiquitin chains when cyclin C translocates to cytoplasm induced by cisplatin treatment. The ubiquitin‐modified cyclin C then anchor at mitochondira, which induced mitochondrial fission and ROS synthesis. Depleting CCNC or mutation on the ubiquitylation sites decreased mitochondrial ROS production and reduced cell apoptosis under cisplatin treatment. Xenograft study showed that disrupting cyclin C ubiquitylation by HACE1 conferred impairing cell apoptosis response upon cisplatin administration. Conclusions Cyclin C is a newly identified substrate of HACE1 E3 ligase. HACE1‐mediated ubiquitylation of cyclin C sheds light on a better understanding of cisplatin‐associated resistance in gastric cancer patients. Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer. With cisplatin‐induced nuclear–mitochondrial translocation of cyclin C, its ubiquitylation by HACE1 increased mitochondrial fission and mitochondrial‐derived oxidative stress, leading to cell apoptosis.https://doi.org/10.1002/ctm2.770cisplatincyclin CHACE1mitochondrial stabilityubiquitylation |
| spellingShingle | Hong‐yue Jiang Ying‐ling Chen Xing‐xing Xu Chuan‐yin Li Yun Chen Dong‐ping Li Xiao‐qing Zeng Hong Gao Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer Clinical and Translational Medicine cisplatin cyclin C HACE1 mitochondrial stability ubiquitylation |
| title | Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer |
| title_full | Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer |
| title_fullStr | Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer |
| title_full_unstemmed | Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer |
| title_short | Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer |
| title_sort | ubiquitylation of cyclin c by hace1 regulates cisplatin associated sensitivity in gastric cancer |
| topic | cisplatin cyclin C HACE1 mitochondrial stability ubiquitylation |
| url | https://doi.org/10.1002/ctm2.770 |
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