HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells

Abstract HACE1, an E3 ubiquitin-protein ligase, is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer. However, its role in glioma remains elusive. Here, we observed increased expression of HACE1 in gliomas related to control subjects, and found...

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Autores principales:	Chenxing Da, Jun Pu, Zhe Liu, Jing Wei, Yiping Qu, Yongxing Wu, Bingyin Shi, Jian Yang, Nongyue He, Peng Hou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Medicine R Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ba8891b4a6314699b53fa292268d5610
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spelling	oai:doaj.org-article:ba8891b4a6314699b53fa292268d56102021-11-28T12:08:42ZHACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells10.1038/s41392-021-00793-z2059-3635https://doaj.org/article/ba8891b4a6314699b53fa292268d56102021-11-01T00:00:00Zhttps://doi.org/10.1038/s41392-021-00793-zhttps://doaj.org/toc/2059-3635Abstract HACE1, an E3 ubiquitin-protein ligase, is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer. However, its role in glioma remains elusive. Here, we observed increased expression of HACE1 in gliomas related to control subjects, and found a strong correlation of high HACE1 expression with poor prognosis in patients with WHO grade III and IV as well as low-grade glioma (LGG) patients receiving radiotherapy. HACE1 knockdown obviously suppressed malignant behaviors of glioma cells, while ectopic expression of HACE1 enhanced cell growth in vitro and in vivo. Further studies revealed that HACE1 enhanced protein stability of nuclear factor erythroid 2-related factor 2 (NRF2) by competitively binding to NRF2 with another E3 ligase KEAP1. Besides, HACE1 also promoted internal ribosome entry site (IRES)-mediated mRNA translation of NRF2. These effects did not depend on its E3 ligase activity. Finally, we demonstrated that HACE1 dramatically reduced cellular ROS levels by activating NRF2, thereby decreasing the response of glioma cells to radiation. Altogether, our data demonstrate that HACE1 causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells by activating NRF2, and indicate that it may act as the role of prognostic factor and potential therapeutic target in glioma.Chenxing DaJun PuZhe LiuJing WeiYiping QuYongxing WuBingyin ShiJian YangNongyue HePeng HouNature Publishing GrouparticleMedicineRBiology (General)QH301-705.5ENSignal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Biology (General) QH301-705.5
spellingShingle	Medicine R Biology (General) QH301-705.5 Chenxing Da Jun Pu Zhe Liu Jing Wei Yiping Qu Yongxing Wu Bingyin Shi Jian Yang Nongyue He Peng Hou HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells
description	Abstract HACE1, an E3 ubiquitin-protein ligase, is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer. However, its role in glioma remains elusive. Here, we observed increased expression of HACE1 in gliomas related to control subjects, and found a strong correlation of high HACE1 expression with poor prognosis in patients with WHO grade III and IV as well as low-grade glioma (LGG) patients receiving radiotherapy. HACE1 knockdown obviously suppressed malignant behaviors of glioma cells, while ectopic expression of HACE1 enhanced cell growth in vitro and in vivo. Further studies revealed that HACE1 enhanced protein stability of nuclear factor erythroid 2-related factor 2 (NRF2) by competitively binding to NRF2 with another E3 ligase KEAP1. Besides, HACE1 also promoted internal ribosome entry site (IRES)-mediated mRNA translation of NRF2. These effects did not depend on its E3 ligase activity. Finally, we demonstrated that HACE1 dramatically reduced cellular ROS levels by activating NRF2, thereby decreasing the response of glioma cells to radiation. Altogether, our data demonstrate that HACE1 causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells by activating NRF2, and indicate that it may act as the role of prognostic factor and potential therapeutic target in glioma.
format	article
author	Chenxing Da Jun Pu Zhe Liu Jing Wei Yiping Qu Yongxing Wu Bingyin Shi Jian Yang Nongyue He Peng Hou
author_facet	Chenxing Da Jun Pu Zhe Liu Jing Wei Yiping Qu Yongxing Wu Bingyin Shi Jian Yang Nongyue He Peng Hou
author_sort	Chenxing Da
title	HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells
title_short	HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells
title_full	HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells
title_fullStr	HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells
title_full_unstemmed	HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells
title_sort	hace1-mediated nrf2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/ba8891b4a6314699b53fa292268d5610
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HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells

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