Cargando…
SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance
The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, ho...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016909/ https://www.ncbi.nlm.nih.gov/pubmed/33795649 http://dx.doi.org/10.1038/s41419-021-03635-6 |
_version_ | 1783673952792477696 |
---|---|
author | Li, Jing Wu, Ruiqin Yung, Mingo M. H. Sun, Jing Li, Zhuqing Yang, Hai Zhang, Yi Liu, Stephanie S. Cheung, Annie N. Y. Ngan, Hextan Y. S. Braisted, John C. Zheng, Wei Wei, Huiqiang Gao, Yingtang Nemes, Peter Pei, Huadong Chan, David W. Li, Yiliang Zhu, Wenge |
author_facet | Li, Jing Wu, Ruiqin Yung, Mingo M. H. Sun, Jing Li, Zhuqing Yang, Hai Zhang, Yi Liu, Stephanie S. Cheung, Annie N. Y. Ngan, Hextan Y. S. Braisted, John C. Zheng, Wei Wei, Huiqiang Gao, Yingtang Nemes, Peter Pei, Huadong Chan, David W. Li, Yiliang Zhu, Wenge |
author_sort | Li, Jing |
collection | PubMed |
description | The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway. |
format | Online Article Text |
id | pubmed-8016909 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-80169092021-04-16 SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance Li, Jing Wu, Ruiqin Yung, Mingo M. H. Sun, Jing Li, Zhuqing Yang, Hai Zhang, Yi Liu, Stephanie S. Cheung, Annie N. Y. Ngan, Hextan Y. S. Braisted, John C. Zheng, Wei Wei, Huiqiang Gao, Yingtang Nemes, Peter Pei, Huadong Chan, David W. Li, Yiliang Zhu, Wenge Cell Death Dis Article The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway. Nature Publishing Group UK 2021-04-01 /pmc/articles/PMC8016909/ /pubmed/33795649 http://dx.doi.org/10.1038/s41419-021-03635-6 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Li, Jing Wu, Ruiqin Yung, Mingo M. H. Sun, Jing Li, Zhuqing Yang, Hai Zhang, Yi Liu, Stephanie S. Cheung, Annie N. Y. Ngan, Hextan Y. S. Braisted, John C. Zheng, Wei Wei, Huiqiang Gao, Yingtang Nemes, Peter Pei, Huadong Chan, David W. Li, Yiliang Zhu, Wenge SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance |
title | SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance |
title_full | SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance |
title_fullStr | SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance |
title_full_unstemmed | SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance |
title_short | SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance |
title_sort | senp1-mediated desumoylation of jak2 regulates its kinase activity and platinum drug resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016909/ https://www.ncbi.nlm.nih.gov/pubmed/33795649 http://dx.doi.org/10.1038/s41419-021-03635-6 |
work_keys_str_mv | AT lijing senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT wuruiqin senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT yungmingomh senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT sunjing senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT lizhuqing senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT yanghai senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT zhangyi senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT liustephanies senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT cheungannieny senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT nganhextanys senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT braistedjohnc senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT zhengwei senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT weihuiqiang senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT gaoyingtang senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT nemespeter senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT peihuadong senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT chandavidw senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT liyiliang senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance AT zhuwenge senp1mediateddesumoylationofjak2regulatesitskinaseactivityandplatinumdrugresistance |