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Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis

Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specifi...

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Autores principales: Zhou, Xuexia, Li, Xuebing, Wang, Run, Hua, Dan, Sun, Cuiyun, Yu, Lin, Shi, Cuijuan, Luo, Wenjun, Jiang, Zhendong, An, Wenzhe, Wang, Qian, Yu, Shizhu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509381/
https://www.ncbi.nlm.nih.gov/pubmed/36153326
http://dx.doi.org/10.1038/s41419-022-05265-y
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author Zhou, Xuexia
Li, Xuebing
Wang, Run
Hua, Dan
Sun, Cuiyun
Yu, Lin
Shi, Cuijuan
Luo, Wenjun
Jiang, Zhendong
An, Wenzhe
Wang, Qian
Yu, Shizhu
author_facet Zhou, Xuexia
Li, Xuebing
Wang, Run
Hua, Dan
Sun, Cuiyun
Yu, Lin
Shi, Cuijuan
Luo, Wenjun
Jiang, Zhendong
An, Wenzhe
Wang, Qian
Yu, Shizhu
author_sort Zhou, Xuexia
collection PubMed
description Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFβ/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFβ/SMAD signalling. Intriguingly, we found that Pontin amplified TGFβR2 gene transcription by recruiting LEF1, thereby activating TGFβ/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFβR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFβR2 gene transcription, which could be exploited to target TGFβ/SMAD signalling for anti-glioma therapy.
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spelling pubmed-95093812022-09-26 Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis Zhou, Xuexia Li, Xuebing Wang, Run Hua, Dan Sun, Cuiyun Yu, Lin Shi, Cuijuan Luo, Wenjun Jiang, Zhendong An, Wenzhe Wang, Qian Yu, Shizhu Cell Death Dis Article Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFβ/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFβ/SMAD signalling. Intriguingly, we found that Pontin amplified TGFβR2 gene transcription by recruiting LEF1, thereby activating TGFβ/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFβR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFβR2 gene transcription, which could be exploited to target TGFβ/SMAD signalling for anti-glioma therapy. Nature Publishing Group UK 2022-09-24 /pmc/articles/PMC9509381/ /pubmed/36153326 http://dx.doi.org/10.1038/s41419-022-05265-y Text en © The Author(s) 2022 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
Zhou, Xuexia
Li, Xuebing
Wang, Run
Hua, Dan
Sun, Cuiyun
Yu, Lin
Shi, Cuijuan
Luo, Wenjun
Jiang, Zhendong
An, Wenzhe
Wang, Qian
Yu, Shizhu
Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
title Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
title_full Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
title_fullStr Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
title_full_unstemmed Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
title_short Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
title_sort recruitment of lef1 by pontin chromatin modifier amplifies tgfbr2 transcription and activates tgfβ/smad signalling during gliomagenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509381/
https://www.ncbi.nlm.nih.gov/pubmed/36153326
http://dx.doi.org/10.1038/s41419-022-05265-y
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