Cargando…
BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation
Cathepsin K inhibitor (odanacatib; ODN) and cathepsin K knockdown (siRNA) enhance oxaliplatin-induced apoptosis through p53-dependent Bax upregulation. However, its underlying mechanisms remain unclear. In this study, we elucidated the mechanism behind enhancement of oxaliplatin-induced apoptosis by...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117696/ https://www.ncbi.nlm.nih.gov/pubmed/35584569 http://dx.doi.org/10.1016/j.redox.2022.102336 |
_version_ | 1784710366240964608 |
---|---|
author | Seo, Seung Un Woo, Seon Min Lee, Seul Gi Kim, Min Yeong Lee, Hyun Shik Choi, Yung Hyun Kim, Sang Hyun Chang, Young-Chae Min, Kyoung-jin Kwon, Taeg Kyu |
author_facet | Seo, Seung Un Woo, Seon Min Lee, Seul Gi Kim, Min Yeong Lee, Hyun Shik Choi, Yung Hyun Kim, Sang Hyun Chang, Young-Chae Min, Kyoung-jin Kwon, Taeg Kyu |
author_sort | Seo, Seung Un |
collection | PubMed |
description | Cathepsin K inhibitor (odanacatib; ODN) and cathepsin K knockdown (siRNA) enhance oxaliplatin-induced apoptosis through p53-dependent Bax upregulation. However, its underlying mechanisms remain unclear. In this study, we elucidated the mechanism behind enhancement of oxaliplatin-induced apoptosis by ODN. We also investigated the molecular mechanisms of ODN-induced Bax upregulation. Here, we demonstrated that ODN-induced Bax upregulation required p53, but it was independent of p53 transcriptional activity. Various mutants of the DNA-binding domain of p53 induced Bax upregulation in ODN-treated cells. p53 functional domain analysis showed that the C-terminal domain of p53 participates in the physical interaction and stabilization of Sp1, a major transcription factor of Bax. We screened a specific siRNA encoding 50 deubiquitinases and identified that BAP1 stabilizes Sp1. The knockdown or catalytic mutant form of BAP1 abolished the ODN-induced upregulation of Sp1 and Bax expression. Mechanistically, ODN induced BAP1 phosphorylation and enhanced Sp1-BAP1 interaction, resulting in Sp1 ubiquitination and degradation. Interestingly, ODN-induced BAP1 phosphorylation and DNA damage were modulated by the production of mitochondrial reactive oxygen species (ROS). Mitochondrial ROS scavengers prevented DNA damage, BAP1-mediated Sp1 stabilization, and Bax upregulation by ODN. BAP1 downregulation by siRNA inhibited apoptosis induced by the combined treatment of ODN and oxaliplatin/etoposide. Therefore, Sp1 is a crucial transcription factor for ODN-induced Bax upregulation, and Sp1 stabilization is regulated by BAP1. |
format | Online Article Text |
id | pubmed-9117696 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-91176962022-05-20 BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation Seo, Seung Un Woo, Seon Min Lee, Seul Gi Kim, Min Yeong Lee, Hyun Shik Choi, Yung Hyun Kim, Sang Hyun Chang, Young-Chae Min, Kyoung-jin Kwon, Taeg Kyu Redox Biol Research Paper Cathepsin K inhibitor (odanacatib; ODN) and cathepsin K knockdown (siRNA) enhance oxaliplatin-induced apoptosis through p53-dependent Bax upregulation. However, its underlying mechanisms remain unclear. In this study, we elucidated the mechanism behind enhancement of oxaliplatin-induced apoptosis by ODN. We also investigated the molecular mechanisms of ODN-induced Bax upregulation. Here, we demonstrated that ODN-induced Bax upregulation required p53, but it was independent of p53 transcriptional activity. Various mutants of the DNA-binding domain of p53 induced Bax upregulation in ODN-treated cells. p53 functional domain analysis showed that the C-terminal domain of p53 participates in the physical interaction and stabilization of Sp1, a major transcription factor of Bax. We screened a specific siRNA encoding 50 deubiquitinases and identified that BAP1 stabilizes Sp1. The knockdown or catalytic mutant form of BAP1 abolished the ODN-induced upregulation of Sp1 and Bax expression. Mechanistically, ODN induced BAP1 phosphorylation and enhanced Sp1-BAP1 interaction, resulting in Sp1 ubiquitination and degradation. Interestingly, ODN-induced BAP1 phosphorylation and DNA damage were modulated by the production of mitochondrial reactive oxygen species (ROS). Mitochondrial ROS scavengers prevented DNA damage, BAP1-mediated Sp1 stabilization, and Bax upregulation by ODN. BAP1 downregulation by siRNA inhibited apoptosis induced by the combined treatment of ODN and oxaliplatin/etoposide. Therefore, Sp1 is a crucial transcription factor for ODN-induced Bax upregulation, and Sp1 stabilization is regulated by BAP1. Elsevier 2022-05-13 /pmc/articles/PMC9117696/ /pubmed/35584569 http://dx.doi.org/10.1016/j.redox.2022.102336 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Seo, Seung Un Woo, Seon Min Lee, Seul Gi Kim, Min Yeong Lee, Hyun Shik Choi, Yung Hyun Kim, Sang Hyun Chang, Young-Chae Min, Kyoung-jin Kwon, Taeg Kyu BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation |
title | BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation |
title_full | BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation |
title_fullStr | BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation |
title_full_unstemmed | BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation |
title_short | BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation |
title_sort | bap1 phosphorylation-mediated sp1 stabilization plays a critical role in cathepsin k inhibition-induced c-terminal p53-dependent bax upregulation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117696/ https://www.ncbi.nlm.nih.gov/pubmed/35584569 http://dx.doi.org/10.1016/j.redox.2022.102336 |
work_keys_str_mv | AT seoseungun bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT wooseonmin bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT leeseulgi bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT kimminyeong bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT leehyunshik bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT choiyunghyun bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT kimsanghyun bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT changyoungchae bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT minkyoungjin bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation AT kwontaegkyu bap1phosphorylationmediatedsp1stabilizationplaysacriticalroleincathepsinkinhibitioninducedcterminalp53dependentbaxupregulation |