DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination
Abstract Chemoresistance is the main obstacle in osteosarcoma (OS) treatment; however, the underlying mechanism remains unclear. In this study, it is discovered that DDRGK domain‐containing protein 1 (DDRGK1) plays a fundamental role in chemoresistance induced in OS. Bioinformatic and tissue analyse...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-05-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202204438 |
| _version_ | 1797825234467815424 |
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| author | Xin Wang Tangjun Zhou Xiao Yang Xiankun Cao Gu Jin Pu Zhang Jiadong Guo Kewei Rong Baixing Li Yibin Hu Kexin Liu Peixiang Ma An Qin Jie Zhao |
| author_facet | Xin Wang Tangjun Zhou Xiao Yang Xiankun Cao Gu Jin Pu Zhang Jiadong Guo Kewei Rong Baixing Li Yibin Hu Kexin Liu Peixiang Ma An Qin Jie Zhao |
| author_sort | Xin Wang |
| collection | DOAJ |
| description | Abstract Chemoresistance is the main obstacle in osteosarcoma (OS) treatment; however, the underlying mechanism remains unclear. In this study, it is discovered that DDRGK domain‐containing protein 1 (DDRGK1) plays a fundamental role in chemoresistance induced in OS. Bioinformatic and tissue analyses indicate that higher expression of DDRGK1 correlates with advanced tumor stage and poor clinical prognosis of OS. Quantitative proteomic analyses suggest that DDRGK1 plays a critical role in mitochondrial oxidative phosphorylation. DDRGK1 knockout trigger the accumulation of reactive oxygen species (ROS) and attenuate the stability of nuclear factor erythroid‐2‐related factor 2 (NRF2), a major antioxidant response element. Furthermore, DDRGK1 inhibits ubiquitin‐proteasome‐mediated degradation of NRF2 via competitive binding to the Kelch‐like ECH‐associated protein 1 (KEAP1) protein, which recruits NRF2 to CULLIN(CUL3). DDRGK1 knockout attenuates NRF2 stability, contributing to ROS accumulation, which promotes apoptosis and enhanced chemosensitivity to doxorubicin (DOX) and etoposide in cancer cells. Indeed, DDRGK1 knockout significantly enhances osteosarcoma chemosensitivity to DOX in vivo. The combination of DDRGK1 knockdown and DOX treatment provides a promising new avenue for the effective treatment of OS. |
| first_indexed | 2024-03-13T10:51:01Z |
| format | Article |
| id | doaj.art-2bf86d2cdb0f4d85a91a9c4aa3c2be67 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-13T10:51:01Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-2bf86d2cdb0f4d85a91a9c4aa3c2be672023-05-17T13:02:05ZengWileyAdvanced Science2198-38442023-05-011014n/an/a10.1002/advs.202204438DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 UbiquitinationXin Wang0Tangjun Zhou1Xiao Yang2Xiankun Cao3Gu Jin4Pu Zhang5Jiadong Guo6Kewei Rong7Baixing Li8Yibin Hu9Kexin Liu10Peixiang Ma11An Qin12Jie Zhao13Shanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaThe Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) Institute of Basic Medicine and Cancer (IBMC) Chinese Academy of Sciences Hangzhou 310022 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaShanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine 639 Zhaizaoju Road Shanghai 200011 P. R. ChinaAbstract Chemoresistance is the main obstacle in osteosarcoma (OS) treatment; however, the underlying mechanism remains unclear. In this study, it is discovered that DDRGK domain‐containing protein 1 (DDRGK1) plays a fundamental role in chemoresistance induced in OS. Bioinformatic and tissue analyses indicate that higher expression of DDRGK1 correlates with advanced tumor stage and poor clinical prognosis of OS. Quantitative proteomic analyses suggest that DDRGK1 plays a critical role in mitochondrial oxidative phosphorylation. DDRGK1 knockout trigger the accumulation of reactive oxygen species (ROS) and attenuate the stability of nuclear factor erythroid‐2‐related factor 2 (NRF2), a major antioxidant response element. Furthermore, DDRGK1 inhibits ubiquitin‐proteasome‐mediated degradation of NRF2 via competitive binding to the Kelch‐like ECH‐associated protein 1 (KEAP1) protein, which recruits NRF2 to CULLIN(CUL3). DDRGK1 knockout attenuates NRF2 stability, contributing to ROS accumulation, which promotes apoptosis and enhanced chemosensitivity to doxorubicin (DOX) and etoposide in cancer cells. Indeed, DDRGK1 knockout significantly enhances osteosarcoma chemosensitivity to DOX in vivo. The combination of DDRGK1 knockdown and DOX treatment provides a promising new avenue for the effective treatment of OS.https://doi.org/10.1002/advs.202204438chemoresistanceDDRGK domain‐containing protein 1doxorubicinosteosarcomaredox homeostasis |
| spellingShingle | Xin Wang Tangjun Zhou Xiao Yang Xiankun Cao Gu Jin Pu Zhang Jiadong Guo Kewei Rong Baixing Li Yibin Hu Kexin Liu Peixiang Ma An Qin Jie Zhao DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination Advanced Science chemoresistance DDRGK domain‐containing protein 1 doxorubicin osteosarcoma redox homeostasis |
| title | DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination |
| title_full | DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination |
| title_fullStr | DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination |
| title_full_unstemmed | DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination |
| title_short | DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1‐Mediated NRF2 Ubiquitination |
| title_sort | ddrgk1 enhances osteosarcoma chemoresistance via inhibiting keap1 mediated nrf2 ubiquitination |
| topic | chemoresistance DDRGK domain‐containing protein 1 doxorubicin osteosarcoma redox homeostasis |
| url | https://doi.org/10.1002/advs.202204438 |
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