NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma

Abstract Background Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic...

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Autores principales:	Xiangsheng Su, Yihang Yang, Qing Yang, Bo Pang, Shicheng Sun, Yanjun Wang, Qiujiang Qiao, Changfa Guo, Huanting Liu, Qi Pang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	NOX4 ROS FOXM1 Aerobic glycolysis Glioblastoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d52e342fa020450d9fbaa053f5d939bd
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spelling	oai:doaj.org-article:d52e342fa020450d9fbaa053f5d939bd2021-11-08T11:01:51ZNOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma10.1186/s12885-021-08933-y1471-2407https://doaj.org/article/d52e342fa020450d9fbaa053f5d939bd2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12885-021-08933-yhttps://doaj.org/toc/1471-2407Abstract Background Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic glycolysis is still not clear. Methods The expression of FOXM1 and NADPH oxidase 4 (NOX4) in normal brain tissues and glioma was detected in data from the TCGA database and in our specimens. The effect of NOX4 on the expression of FOXM1 was determined by Western blot, qPCR, reactive oxygen species (ROS) production assays, and luciferase assays. The functions of NOX4 and FOXM1 in aerobic glycolysis in glioblastoma cells were determined by a series of experiments, such as Western blot, extracellular acidification rate (ECAR), lactate production, and intracellular ATP level assays. A xenograft mouse model was established to test our findings in vivo. Results The expression of FOXM1 and NOX4 was increased in glioma specimens compared with normal brain tissues and correlated with poor clinical outcomes. Aberrant mitochondrial reactive oxygen species (ROS) generation of NOX4 induced FOXM1 expression. Mechanistic studies demonstrated that NOX4-derived MitoROS exert their regulatory role on FOXM1 by mediating hypoxia-inducible factor 1α (HIF-1α) stabilization. Further research showed that NOX4-derived MitoROS-induced HIF-1α directly activates the transcription of FOXM1 and results in increased FOXM1 expression. Overexpression of NOX4 or FOXM1 promoted aerobic glycolysis, whereas knockdown of NOX4 or FOXM1 significantly suppressed aerobic glycolysis, in glioblastoma cells. NOX4-induced aerobic glycolysis was dependent on elevated FOXM1 expression, as FOXM1 knockdown abolished NOX4-induced aerobic glycolysis in glioblastoma cells both in vitro and in vivo. Conclusion Increased expression of FOXM1 induced by NOX4-derived MitoROS plays a pivotal role in aerobic glycolysis, and our findings suggest that inhibition of NOX4-FOXM1 signaling may present a potential therapeutic target for glioblastoma treatment.Xiangsheng SuYihang YangQing YangBo PangShicheng SunYanjun WangQiujiang QiaoChangfa GuoHuanting LiuQi PangBMCarticleNOX4ROSFOXM1Aerobic glycolysisGlioblastomaNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBMC Cancer, Vol 21, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NOX4 ROS FOXM1 Aerobic glycolysis Glioblastoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	NOX4 ROS FOXM1 Aerobic glycolysis Glioblastoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Xiangsheng Su Yihang Yang Qing Yang Bo Pang Shicheng Sun Yanjun Wang Qiujiang Qiao Changfa Guo Huanting Liu Qi Pang NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma
description	Abstract Background Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic glycolysis is still not clear. Methods The expression of FOXM1 and NADPH oxidase 4 (NOX4) in normal brain tissues and glioma was detected in data from the TCGA database and in our specimens. The effect of NOX4 on the expression of FOXM1 was determined by Western blot, qPCR, reactive oxygen species (ROS) production assays, and luciferase assays. The functions of NOX4 and FOXM1 in aerobic glycolysis in glioblastoma cells were determined by a series of experiments, such as Western blot, extracellular acidification rate (ECAR), lactate production, and intracellular ATP level assays. A xenograft mouse model was established to test our findings in vivo. Results The expression of FOXM1 and NOX4 was increased in glioma specimens compared with normal brain tissues and correlated with poor clinical outcomes. Aberrant mitochondrial reactive oxygen species (ROS) generation of NOX4 induced FOXM1 expression. Mechanistic studies demonstrated that NOX4-derived MitoROS exert their regulatory role on FOXM1 by mediating hypoxia-inducible factor 1α (HIF-1α) stabilization. Further research showed that NOX4-derived MitoROS-induced HIF-1α directly activates the transcription of FOXM1 and results in increased FOXM1 expression. Overexpression of NOX4 or FOXM1 promoted aerobic glycolysis, whereas knockdown of NOX4 or FOXM1 significantly suppressed aerobic glycolysis, in glioblastoma cells. NOX4-induced aerobic glycolysis was dependent on elevated FOXM1 expression, as FOXM1 knockdown abolished NOX4-induced aerobic glycolysis in glioblastoma cells both in vitro and in vivo. Conclusion Increased expression of FOXM1 induced by NOX4-derived MitoROS plays a pivotal role in aerobic glycolysis, and our findings suggest that inhibition of NOX4-FOXM1 signaling may present a potential therapeutic target for glioblastoma treatment.
format	article
author	Xiangsheng Su Yihang Yang Qing Yang Bo Pang Shicheng Sun Yanjun Wang Qiujiang Qiao Changfa Guo Huanting Liu Qi Pang
author_facet	Xiangsheng Su Yihang Yang Qing Yang Bo Pang Shicheng Sun Yanjun Wang Qiujiang Qiao Changfa Guo Huanting Liu Qi Pang
author_sort	Xiangsheng Su
title	NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma
title_short	NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma
title_full	NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma
title_fullStr	NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma
title_full_unstemmed	NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma
title_sort	nox4-derived ros-induced overexpression of foxm1 regulates aerobic glycolysis in glioblastoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/d52e342fa020450d9fbaa053f5d939bd
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NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma

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