Cargando…

UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma

The treatment for hepatocellular carcinoma (HCC) is promising in recent years, but still facing critical challenges. The first targeted therapy, sorafenib, prolonged the overall survival by months. However, resistance often occurs, largely limits its efficacy. Sorafenib was found to target the elect...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Junjie, Ji, Lin, Ruan, Yeling, Wan, Zhe, Lin, Zhongjie, Xia, Shunjie, Tao, Liye, Zheng, Junhao, Cai, Liuxin, Wang, Yifan, Liang, Xiao, Cai, Xiujun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129126/
https://www.ncbi.nlm.nih.gov/pubmed/34001851
http://dx.doi.org/10.1038/s41392-021-00594-4
_version_ 1783694246391316480
author Xu, Junjie
Ji, Lin
Ruan, Yeling
Wan, Zhe
Lin, Zhongjie
Xia, Shunjie
Tao, Liye
Zheng, Junhao
Cai, Liuxin
Wang, Yifan
Liang, Xiao
Cai, Xiujun
author_facet Xu, Junjie
Ji, Lin
Ruan, Yeling
Wan, Zhe
Lin, Zhongjie
Xia, Shunjie
Tao, Liye
Zheng, Junhao
Cai, Liuxin
Wang, Yifan
Liang, Xiao
Cai, Xiujun
author_sort Xu, Junjie
collection PubMed
description The treatment for hepatocellular carcinoma (HCC) is promising in recent years, but still facing critical challenges. The first targeted therapy, sorafenib, prolonged the overall survival by months. However, resistance often occurs, largely limits its efficacy. Sorafenib was found to target the electron transport chain complexes, which results in the generation of reactive oxygen species (ROS). To maintain sorafenib resistance and further facilitate tumor progression, cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death. In the present study, we investigated the roles of ROS in sorafenib resistance, and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells. Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib. However, cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells. Further investigation attributed this finding to decreased mitochondrial biogenesis, likely caused by the accelerated degradation of peroxisome proliferator-activated receptor γ coactivator 1β (PGC1β). Mechanistic dissection showed that upregulated UBQLN1 induced PGC1β degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment. Furthermore, clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival. In conclusion, we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance, which may offer new therapeutic targets and strategies for HCC patients.
format Online
Article
Text
id pubmed-8129126
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-81291262021-05-27 UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma Xu, Junjie Ji, Lin Ruan, Yeling Wan, Zhe Lin, Zhongjie Xia, Shunjie Tao, Liye Zheng, Junhao Cai, Liuxin Wang, Yifan Liang, Xiao Cai, Xiujun Signal Transduct Target Ther Article The treatment for hepatocellular carcinoma (HCC) is promising in recent years, but still facing critical challenges. The first targeted therapy, sorafenib, prolonged the overall survival by months. However, resistance often occurs, largely limits its efficacy. Sorafenib was found to target the electron transport chain complexes, which results in the generation of reactive oxygen species (ROS). To maintain sorafenib resistance and further facilitate tumor progression, cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death. In the present study, we investigated the roles of ROS in sorafenib resistance, and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells. Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib. However, cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells. Further investigation attributed this finding to decreased mitochondrial biogenesis, likely caused by the accelerated degradation of peroxisome proliferator-activated receptor γ coactivator 1β (PGC1β). Mechanistic dissection showed that upregulated UBQLN1 induced PGC1β degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment. Furthermore, clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival. In conclusion, we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance, which may offer new therapeutic targets and strategies for HCC patients. Nature Publishing Group UK 2021-05-18 /pmc/articles/PMC8129126/ /pubmed/34001851 http://dx.doi.org/10.1038/s41392-021-00594-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Xu, Junjie
Ji, Lin
Ruan, Yeling
Wan, Zhe
Lin, Zhongjie
Xia, Shunjie
Tao, Liye
Zheng, Junhao
Cai, Liuxin
Wang, Yifan
Liang, Xiao
Cai, Xiujun
UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma
title UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma
title_full UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma
title_fullStr UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma
title_full_unstemmed UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma
title_short UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma
title_sort ubqln1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ros homeostasis by targeting pgc1β in hepatocellular carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129126/
https://www.ncbi.nlm.nih.gov/pubmed/34001851
http://dx.doi.org/10.1038/s41392-021-00594-4
work_keys_str_mv AT xujunjie ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT jilin ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT ruanyeling ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT wanzhe ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT linzhongjie ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT xiashunjie ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT taoliye ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT zhengjunhao ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT cailiuxin ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT wangyifan ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT liangxiao ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma
AT caixiujun ubqln1mediatessorafenibresistancethroughregulatingmitochondrialbiogenesisandroshomeostasisbytargetingpgc1binhepatocellularcarcinoma