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Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common soft tissue sarcoma. The identification of the molecular mechanisms regulating GIST progression is vital for its treatment and prevention. Increasing reports have demonstrated that epigenetic alterations play critical roles in GIS...

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Autores principales: Hu, Fuqing, Li, Haijie, Liu, Lu, Xu, Feng, Lai, Senyan, Luo, Xuelai, Hu, Junbo, Yang, Xi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065154/
https://www.ncbi.nlm.nih.gov/pubmed/30060750
http://dx.doi.org/10.1186/s12943-018-0861-6
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author Hu, Fuqing
Li, Haijie
Liu, Lu
Xu, Feng
Lai, Senyan
Luo, Xuelai
Hu, Junbo
Yang, Xi
author_facet Hu, Fuqing
Li, Haijie
Liu, Lu
Xu, Feng
Lai, Senyan
Luo, Xuelai
Hu, Junbo
Yang, Xi
author_sort Hu, Fuqing
collection PubMed
description BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common soft tissue sarcoma. The identification of the molecular mechanisms regulating GIST progression is vital for its treatment and prevention. Increasing reports have demonstrated that epigenetic alterations play critical roles in GIST development. However, the role of the histone demethylase KDM4D in GIST progression is poorly understood. METHODS: In clinically matched GIST tissues, KDM4D protein levels were measured by Western blot and immunohistochemical (IHC) staining. KDM4D mRNA levels were examined by quantitative real-time PCR (qRT-PCR). Bioinformatics analysis was used to examine KDM4D expression. The biological effects of KDM4D were investigated in vitro using CCK-8, BrdU/PI, wound healing, colony formation, tube formation and Transwell assays and in vivo using a xenograft mice model. Luciferase assays were used to assess regulation of HIF1β gene promoter activity by KDM4D. ChIP assays were performed to assess KDM4D, H3K36me3 and H3K9me3 occupancy on the HIF1β gene promoter. RESULTS: We observed a significant upregulation of KDM4D in GIST tissue compared with matched normal tissue and further explored the oncogenic function of KDM4D both in vitro and in vivo. Furthermore, we demonstrated that KDM4D directly interacted with the HIF1β gene promoter and regulated its activity, promoting tumour angiogenesis and GIST progression both in vitro and in vivo. Finally, we demonstrated that KDM4D transcriptionally activates HIF1β expression via H3K9me3 and H3K36me3 demethylation at the promoter region. CONCLUSIONS: Our findings reveal the important roles of the KDM4D/HIF1β/VEGFA signalling pathway in GIST progression, and this pathway may act as a potential therapeutic target for GIST patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12943-018-0861-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-60651542018-08-01 Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling Hu, Fuqing Li, Haijie Liu, Lu Xu, Feng Lai, Senyan Luo, Xuelai Hu, Junbo Yang, Xi Mol Cancer Research BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common soft tissue sarcoma. The identification of the molecular mechanisms regulating GIST progression is vital for its treatment and prevention. Increasing reports have demonstrated that epigenetic alterations play critical roles in GIST development. However, the role of the histone demethylase KDM4D in GIST progression is poorly understood. METHODS: In clinically matched GIST tissues, KDM4D protein levels were measured by Western blot and immunohistochemical (IHC) staining. KDM4D mRNA levels were examined by quantitative real-time PCR (qRT-PCR). Bioinformatics analysis was used to examine KDM4D expression. The biological effects of KDM4D were investigated in vitro using CCK-8, BrdU/PI, wound healing, colony formation, tube formation and Transwell assays and in vivo using a xenograft mice model. Luciferase assays were used to assess regulation of HIF1β gene promoter activity by KDM4D. ChIP assays were performed to assess KDM4D, H3K36me3 and H3K9me3 occupancy on the HIF1β gene promoter. RESULTS: We observed a significant upregulation of KDM4D in GIST tissue compared with matched normal tissue and further explored the oncogenic function of KDM4D both in vitro and in vivo. Furthermore, we demonstrated that KDM4D directly interacted with the HIF1β gene promoter and regulated its activity, promoting tumour angiogenesis and GIST progression both in vitro and in vivo. Finally, we demonstrated that KDM4D transcriptionally activates HIF1β expression via H3K9me3 and H3K36me3 demethylation at the promoter region. CONCLUSIONS: Our findings reveal the important roles of the KDM4D/HIF1β/VEGFA signalling pathway in GIST progression, and this pathway may act as a potential therapeutic target for GIST patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12943-018-0861-6) contains supplementary material, which is available to authorized users. BioMed Central 2018-07-30 /pmc/articles/PMC6065154/ /pubmed/30060750 http://dx.doi.org/10.1186/s12943-018-0861-6 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Hu, Fuqing
Li, Haijie
Liu, Lu
Xu, Feng
Lai, Senyan
Luo, Xuelai
Hu, Junbo
Yang, Xi
Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling
title Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling
title_full Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling
title_fullStr Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling
title_full_unstemmed Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling
title_short Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling
title_sort histone demethylase kdm4d promotes gastrointestinal stromal tumor progression through hif1β/vegfa signalling
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065154/
https://www.ncbi.nlm.nih.gov/pubmed/30060750
http://dx.doi.org/10.1186/s12943-018-0861-6
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