HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas

BackgroundCheckpoint blockade therapies targeting programmed death ligand 1 (PD-L1) and its receptor programmed cell death 1 promote T cell-mediated immune surveillance against tumors and have been associated with significant clinical benefit in cancer patients. The long-stranded non-coding RNA HOTA...

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Autores principales:	Yunfei Wang, Kaikai Yi, Xing Liu, Yanli Tan, Weili Jin, Yansheng Li, Junhu Zhou, Hongjun Wang, Chunsheng Kang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	HOTAIR chromatin structure NF-κB activation immunoescape inflammatory signaling pathway Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/6e72c5e777a348118a3ce1ca60c55667
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spelling	oai:doaj.org-article:6e72c5e777a348118a3ce1ca60c556672021-11-30T12:01:07ZHOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas1664-322410.3389/fimmu.2021.785463https://doaj.org/article/6e72c5e777a348118a3ce1ca60c556672021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.785463/fullhttps://doaj.org/toc/1664-3224BackgroundCheckpoint blockade therapies targeting programmed death ligand 1 (PD-L1) and its receptor programmed cell death 1 promote T cell-mediated immune surveillance against tumors and have been associated with significant clinical benefit in cancer patients. The long-stranded non-coding RNA HOTAIR is highly expressed and associated with metastasis in a variety of cancer types and promotes tumor metastasis at least in part through association with the PRC2 complex that induces redirection to hundreds of genes involved in tumor metastasis. Here, we report that HOTAIR is an activator lncRNA of the NF-κB pathway and demonstrate that its apparent upregulation promotes inflammatory signaling and immune escape in glioma cells.MethodsBioinformatics analysis was used to elucidate the relationship between HOTAIR and NF-κB pathway in HOTAIR knockdown glioma cells. At the cytological level, protein hybridization and immunofluorescence were used to detect the response of proteins in the NF-κB signaling pathway to HOTAIR regulation. ChIP and ChIRP experiments identified HOTAIR target genes. Animal experiments verified alterations in inflammation and immune escape following HOTAIR knockdown and activity inhibition.ResultsHOTAIR activated the expression of proteins involved in NF-κB, TNFα, MAPK and other inflammatory signaling pathways. In addition, HOTAIR induced various proteins containing protein kinase structural domains and promoted the enrichment of proteins and complexes of important inflammatory signaling pathways, such as the TNFα/NF-κB signaling protein complex, the IκB kinase complex, and the IKKA-IKKB complex. In addition, HOTAIR aberrantly activated biological processes involved in glioma immune responses, T-cell co-stimulation and transcription initiation by RNA polymerase II. HOTAIR facilitated the induction of IκBα phosphorylation by suppressing the expression of the NF-κB upstream protein UBXN1, promoting NF-κB phosphorylation and nuclear translocation. In vivo, reduction of HOTAIR decreased PD-L1 protein expression, indicating that cells are more likely to be targeted by immune T cells.ConclusionIn conclusion, our results provide convincing evidence that lncRNA HOTAIR drives aberrant gene transcription and immune escape from tumor cells through the NF-κB pathway.Yunfei WangYunfei WangKaikai YiKaikai YiKaikai YiKaikai YiXing LiuYanli TanYanli TanWeili JinWeili JinYansheng LiYansheng LiJunhu ZhouJunhu ZhouHongjun WangChunsheng KangChunsheng KangFrontiers Media S.A.articleHOTAIRchromatin structureNF-κB activationimmunoescapeinflammatory signaling pathwayImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HOTAIR chromatin structure NF-κB activation immunoescape inflammatory signaling pathway Immunologic diseases. Allergy RC581-607
spellingShingle	HOTAIR chromatin structure NF-κB activation immunoescape inflammatory signaling pathway Immunologic diseases. Allergy RC581-607 Yunfei Wang Yunfei Wang Kaikai Yi Kaikai Yi Kaikai Yi Kaikai Yi Xing Liu Yanli Tan Yanli Tan Weili Jin Weili Jin Yansheng Li Yansheng Li Junhu Zhou Junhu Zhou Hongjun Wang Chunsheng Kang Chunsheng Kang HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas
description	BackgroundCheckpoint blockade therapies targeting programmed death ligand 1 (PD-L1) and its receptor programmed cell death 1 promote T cell-mediated immune surveillance against tumors and have been associated with significant clinical benefit in cancer patients. The long-stranded non-coding RNA HOTAIR is highly expressed and associated with metastasis in a variety of cancer types and promotes tumor metastasis at least in part through association with the PRC2 complex that induces redirection to hundreds of genes involved in tumor metastasis. Here, we report that HOTAIR is an activator lncRNA of the NF-κB pathway and demonstrate that its apparent upregulation promotes inflammatory signaling and immune escape in glioma cells.MethodsBioinformatics analysis was used to elucidate the relationship between HOTAIR and NF-κB pathway in HOTAIR knockdown glioma cells. At the cytological level, protein hybridization and immunofluorescence were used to detect the response of proteins in the NF-κB signaling pathway to HOTAIR regulation. ChIP and ChIRP experiments identified HOTAIR target genes. Animal experiments verified alterations in inflammation and immune escape following HOTAIR knockdown and activity inhibition.ResultsHOTAIR activated the expression of proteins involved in NF-κB, TNFα, MAPK and other inflammatory signaling pathways. In addition, HOTAIR induced various proteins containing protein kinase structural domains and promoted the enrichment of proteins and complexes of important inflammatory signaling pathways, such as the TNFα/NF-κB signaling protein complex, the IκB kinase complex, and the IKKA-IKKB complex. In addition, HOTAIR aberrantly activated biological processes involved in glioma immune responses, T-cell co-stimulation and transcription initiation by RNA polymerase II. HOTAIR facilitated the induction of IκBα phosphorylation by suppressing the expression of the NF-κB upstream protein UBXN1, promoting NF-κB phosphorylation and nuclear translocation. In vivo, reduction of HOTAIR decreased PD-L1 protein expression, indicating that cells are more likely to be targeted by immune T cells.ConclusionIn conclusion, our results provide convincing evidence that lncRNA HOTAIR drives aberrant gene transcription and immune escape from tumor cells through the NF-κB pathway.
format	article
author	Yunfei Wang Yunfei Wang Kaikai Yi Kaikai Yi Kaikai Yi Kaikai Yi Xing Liu Yanli Tan Yanli Tan Weili Jin Weili Jin Yansheng Li Yansheng Li Junhu Zhou Junhu Zhou Hongjun Wang Chunsheng Kang Chunsheng Kang
author_facet	Yunfei Wang Yunfei Wang Kaikai Yi Kaikai Yi Kaikai Yi Kaikai Yi Xing Liu Yanli Tan Yanli Tan Weili Jin Weili Jin Yansheng Li Yansheng Li Junhu Zhou Junhu Zhou Hongjun Wang Chunsheng Kang Chunsheng Kang
author_sort	Yunfei Wang
title	HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas
title_short	HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas
title_full	HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas
title_fullStr	HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas
title_full_unstemmed	HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas
title_sort	hotair up-regulation activates nf-κb to induce immunoescape in gliomas
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/6e72c5e777a348118a3ce1ca60c55667
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HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas

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