Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma
The potential to overcome resistance to proteasome inhibitors is greatly related with ubiquitin-proteasome system during multiple myeloma (MM) treatment process. The constitutive photomorphogenic 1 (RFWD2), referred to an E3 ubiquitin ligase, has been identified as an oncogene in multiple cancers, y...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-04-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.675939/full |
| _version_ | 1818956386383429632 |
|---|---|
| author | Mengjie Guo Mengjie Guo Pinggang Ding Zhen Zhu Lu Fan Yanyan Zhou Shu Yang Ye Yang Chunyan Gu Chunyan Gu |
| author_facet | Mengjie Guo Mengjie Guo Pinggang Ding Zhen Zhu Lu Fan Yanyan Zhou Shu Yang Ye Yang Chunyan Gu Chunyan Gu |
| author_sort | Mengjie Guo |
| collection | DOAJ |
| description | The potential to overcome resistance to proteasome inhibitors is greatly related with ubiquitin-proteasome system during multiple myeloma (MM) treatment process. The constitutive photomorphogenic 1 (RFWD2), referred to an E3 ubiquitin ligase, has been identified as an oncogene in multiple cancers, yet important questions on the role of RFWD2 in MM biology and treatment remain unclear. Here we demonstrated that MM patients with elevated RFWD2 expression achieved adverse outcome and drug resistance by analyzing gene expression profiling. Moreover, we proved that RFWD2 participated in the process of cell cycle, cell growth and death in MM by mass spectrometry analysis. In vitro study indicated that inducible knockdown of RFWD2 hindered cellular growth and triggered apoptosis in MM cells. Mechanism study revealed that RFWD2 controlled MM cellular proliferation via regulating the degradation of P27 rather than P53. Further exploration unveiled that RFWD2 meditated P27 ubiquitination via interacting with RCHY1, which served as an E3 ubiquitin ligase of P27. Finally, in vivo study illustrated that blocking RFWD2 in BTZ-resistant MM cells overcame the drug resistance in a myeloma xenograft mouse model. Taken together, these findings provide compelling evidence for prompting that targeting RFWD2 may be an effective strategy to inhibit cellular proliferation and overcome drug resistance to proteasome inhibitor in MM. |
| first_indexed | 2024-12-20T10:53:08Z |
| format | Article |
| id | doaj.art-59da5d680dd24f90b93544a02d132871 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-20T10:53:08Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-59da5d680dd24f90b93544a02d1328712022-12-21T19:43:12ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-04-01910.3389/fcell.2021.675939675939Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple MyelomaMengjie Guo0Mengjie Guo1Pinggang Ding2Zhen Zhu3Lu Fan4Yanyan Zhou5Shu Yang6Ye Yang7Chunyan Gu8Chunyan Gu9School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaLarge Data Center, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaCollege of Health and Rehabilitation & College of Acupuncture and Massage, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaLarge Data Center, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaThe potential to overcome resistance to proteasome inhibitors is greatly related with ubiquitin-proteasome system during multiple myeloma (MM) treatment process. The constitutive photomorphogenic 1 (RFWD2), referred to an E3 ubiquitin ligase, has been identified as an oncogene in multiple cancers, yet important questions on the role of RFWD2 in MM biology and treatment remain unclear. Here we demonstrated that MM patients with elevated RFWD2 expression achieved adverse outcome and drug resistance by analyzing gene expression profiling. Moreover, we proved that RFWD2 participated in the process of cell cycle, cell growth and death in MM by mass spectrometry analysis. In vitro study indicated that inducible knockdown of RFWD2 hindered cellular growth and triggered apoptosis in MM cells. Mechanism study revealed that RFWD2 controlled MM cellular proliferation via regulating the degradation of P27 rather than P53. Further exploration unveiled that RFWD2 meditated P27 ubiquitination via interacting with RCHY1, which served as an E3 ubiquitin ligase of P27. Finally, in vivo study illustrated that blocking RFWD2 in BTZ-resistant MM cells overcame the drug resistance in a myeloma xenograft mouse model. Taken together, these findings provide compelling evidence for prompting that targeting RFWD2 may be an effective strategy to inhibit cellular proliferation and overcome drug resistance to proteasome inhibitor in MM.https://www.frontiersin.org/articles/10.3389/fcell.2021.675939/fullmultiple myelomaRFWD2proliferationdrug resistanceP27ubiquitination |
| spellingShingle | Mengjie Guo Mengjie Guo Pinggang Ding Zhen Zhu Lu Fan Yanyan Zhou Shu Yang Ye Yang Chunyan Gu Chunyan Gu Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma Frontiers in Cell and Developmental Biology multiple myeloma RFWD2 proliferation drug resistance P27 ubiquitination |
| title | Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma |
| title_full | Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma |
| title_fullStr | Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma |
| title_full_unstemmed | Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma |
| title_short | Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma |
| title_sort | targeting rfwd2 as an effective strategy to inhibit cellular proliferation and overcome drug resistance to proteasome inhibitor in multiple myeloma |
| topic | multiple myeloma RFWD2 proliferation drug resistance P27 ubiquitination |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.675939/full |
| work_keys_str_mv | AT mengjieguo targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT mengjieguo targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT pinggangding targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT zhenzhu targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT lufan targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT yanyanzhou targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT shuyang targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT yeyang targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT chunyangu targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma AT chunyangu targetingrfwd2asaneffectivestrategytoinhibitcellularproliferationandovercomedrugresistancetoproteasomeinhibitorinmultiplemyeloma |