FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in context
Background: The transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-07-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419304037 |
| _version_ | 1819327153727078400 |
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| author | Kai-Chun Cheng Ruey-Jen Lin Jing-Yan Cheng Sheng-Hung Wang Jyh-Cherng Yu Jen-Chine Wu Yuh-Jin Liang Huan-Ming Hsu John Yu Alice L. Yu |
| author_facet | Kai-Chun Cheng Ruey-Jen Lin Jing-Yan Cheng Sheng-Hung Wang Jyh-Cherng Yu Jen-Chine Wu Yuh-Jin Liang Huan-Ming Hsu John Yu Alice L. Yu |
| author_sort | Kai-Chun Cheng |
| collection | DOAJ |
| description | Background: The transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2 has been considered as a key pharmacological target. Unfortunately, there are no specific Nrf2 inhibitors for therapeutic application. Moreover, high Nrf2 activity in many tumors without Keap1 or Nrf2 mutations suggests that alternative mechanisms of Nrf2 regulation exist. Methods: Interaction of FAM129B with Keap1 is demonstrated by immunofluorescence, colocalization, co-immunoprecipitation and mammalian two-hybrid assay. Antioxidative function of FAM129B is analyzed by measuring ROS levels with DCF/flow cytometry, Nrf2 activation using luciferase reporter assay and determination of downstream gene expression by qPCR and wester blotting. Impact of FAM129B on in vivo chemosensitivity is examined in mice bearing breast and colon cancer xenografts. The clinical relevance of FAM129B is assessed by qPCR in breast cancer samples and data mining of publicly available databases. Findings: We have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer. Interpretation: These findings demonstrate the important role of FAM129B in Nrf2 activation and antioxidative response, and identify FMA129B as a potential therapeutic target. Fund: The Chang Gung Medical Foundation (Taiwan) and the Ministry of Science and Technology (Taiwan). Keywords: FAM129B, Nrf2, Keap1, Antioxidation, Chemosensitivity |
| first_indexed | 2024-12-24T13:06:19Z |
| format | Article |
| id | doaj.art-fe4a623bd21a46bc8e0acc2b1b171009 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-24T13:06:19Z |
| publishDate | 2019-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-fe4a623bd21a46bc8e0acc2b1b1710092022-12-21T16:54:00ZengElsevierEBioMedicine2352-39642019-07-01452538FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in contextKai-Chun Cheng0Ruey-Jen Lin1Jing-Yan Cheng2Sheng-Hung Wang3Jyh-Cherng Yu4Jen-Chine Wu5Yuh-Jin Liang6Huan-Ming Hsu7John Yu8Alice L. Yu9Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, TaiwanInstitute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, TaiwanInstitute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, TaiwanInstitute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, TaiwanGeneral Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanInstitute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, TaiwanTranslational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, TaiwanGeneral Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanInstitute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, TaiwanInstitute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan; Department of Pediatrics, University of California in San Diego, San Diego, CA, USA; Corresponding author at: Institute of Stem Cell & Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 33305, Taiwan.Background: The transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2 has been considered as a key pharmacological target. Unfortunately, there are no specific Nrf2 inhibitors for therapeutic application. Moreover, high Nrf2 activity in many tumors without Keap1 or Nrf2 mutations suggests that alternative mechanisms of Nrf2 regulation exist. Methods: Interaction of FAM129B with Keap1 is demonstrated by immunofluorescence, colocalization, co-immunoprecipitation and mammalian two-hybrid assay. Antioxidative function of FAM129B is analyzed by measuring ROS levels with DCF/flow cytometry, Nrf2 activation using luciferase reporter assay and determination of downstream gene expression by qPCR and wester blotting. Impact of FAM129B on in vivo chemosensitivity is examined in mice bearing breast and colon cancer xenografts. The clinical relevance of FAM129B is assessed by qPCR in breast cancer samples and data mining of publicly available databases. Findings: We have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer. Interpretation: These findings demonstrate the important role of FAM129B in Nrf2 activation and antioxidative response, and identify FMA129B as a potential therapeutic target. Fund: The Chang Gung Medical Foundation (Taiwan) and the Ministry of Science and Technology (Taiwan). Keywords: FAM129B, Nrf2, Keap1, Antioxidation, Chemosensitivityhttp://www.sciencedirect.com/science/article/pii/S2352396419304037 |
| spellingShingle | Kai-Chun Cheng Ruey-Jen Lin Jing-Yan Cheng Sheng-Hung Wang Jyh-Cherng Yu Jen-Chine Wu Yuh-Jin Liang Huan-Ming Hsu John Yu Alice L. Yu FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in context EBioMedicine |
| title | FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in context |
| title_full | FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in context |
| title_fullStr | FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in context |
| title_full_unstemmed | FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in context |
| title_short | FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 bindingResearch in context |
| title_sort | fam129b an antioxidative protein reduces chemosensitivity by competing with nrf2 for keap1 bindingresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419304037 |
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