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GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression

BACKGROUND: Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic ge...

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Autores principales: Yang, Xiayun, Zhang, Qin, Li, Shuxuan, Devarajan, Raman, Luo, Binjie, Tan, Zenglai, Wang, Zixian, Giannareas, Nikolaos, Wenta, Tomasz, Ma, Wenlong, Li, Yuqing, Yang, Yuehong, Manninen, Aki, Wu, Song, Wei, Gong-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10408074/
https://www.ncbi.nlm.nih.gov/pubmed/37550764
http://dx.doi.org/10.1186/s13046-023-02745-7
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author Yang, Xiayun
Zhang, Qin
Li, Shuxuan
Devarajan, Raman
Luo, Binjie
Tan, Zenglai
Wang, Zixian
Giannareas, Nikolaos
Wenta, Tomasz
Ma, Wenlong
Li, Yuqing
Yang, Yuehong
Manninen, Aki
Wu, Song
Wei, Gong-Hong
author_facet Yang, Xiayun
Zhang, Qin
Li, Shuxuan
Devarajan, Raman
Luo, Binjie
Tan, Zenglai
Wang, Zixian
Giannareas, Nikolaos
Wenta, Tomasz
Ma, Wenlong
Li, Yuqing
Yang, Yuehong
Manninen, Aki
Wu, Song
Wei, Gong-Hong
author_sort Yang, Xiayun
collection PubMed
description BACKGROUND: Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic genomic event cooperates with inherited germline variants contribute to cancer predisposition and progression. METHODS: We applied integrated genomic and clinical data, experimental models and bioinformatic analysis to identify GATA2 as a highly prevalent metastasis-associated genomic amplification in PCa. Biological roles of GATA2 in PCa metastasis was determined in vitro and in vivo. Global chromatin co-occupancy and co-regulation of GATA2 and SMAD4 was investigated by coimmunoprecipitation, ChIP-seq and RNA-seq assays. Tumor cellular assays, qRT-PCR, western blot, ChIP, luciferase assays and CRISPR-Cas9 editing methods were performed to mechanistically understand the cooperation of GATA2 with SMAD4 in promoting TGFβ1 and AR signaling and mediating inherited PCa risk and progression. RESULTS: In this study, by integrated genomics and experimental analysis, we identified GATA2 as a prevalent metastasis-associated genomic amplification to transcriptionally augment its own expression in PCa. Functional experiments demonstrated that GATA2 physically interacted and cooperated with SMAD4 for genome-wide chromatin co-occupancy and co-regulation of PCa genes and metastasis pathways like TGFβ signaling. Mechanistically, GATA2 was cooperative with SMAD4 to enhance TGFβ and AR signaling pathways, and activated the expression of TGFβ1 via directly binding to a distal enhancer of TGFβ1. Strinkingly, GATA2 and SMAD4 globally mediated inherited PCa risk and formed a transcriptional complex with HOXB13 at the PCa risk-associated rs339331/6q22 enhancer, leading to increased expression of the PCa susceptibility gene RFX6. CONCLUSIONS: Our study prioritizes causal genomic amplification genes with prognostic values in PCa and reveals the pivotal roles of GATA2 in transcriptionally activating the expression of its own and TGFβ1, thereby co-opting to TGFβ1/SMAD4 signaling and RFX6 at 6q22 to modulate PCa predisposition and progression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02745-7.
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spelling pubmed-104080742023-08-09 GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression Yang, Xiayun Zhang, Qin Li, Shuxuan Devarajan, Raman Luo, Binjie Tan, Zenglai Wang, Zixian Giannareas, Nikolaos Wenta, Tomasz Ma, Wenlong Li, Yuqing Yang, Yuehong Manninen, Aki Wu, Song Wei, Gong-Hong J Exp Clin Cancer Res Research BACKGROUND: Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic genomic event cooperates with inherited germline variants contribute to cancer predisposition and progression. METHODS: We applied integrated genomic and clinical data, experimental models and bioinformatic analysis to identify GATA2 as a highly prevalent metastasis-associated genomic amplification in PCa. Biological roles of GATA2 in PCa metastasis was determined in vitro and in vivo. Global chromatin co-occupancy and co-regulation of GATA2 and SMAD4 was investigated by coimmunoprecipitation, ChIP-seq and RNA-seq assays. Tumor cellular assays, qRT-PCR, western blot, ChIP, luciferase assays and CRISPR-Cas9 editing methods were performed to mechanistically understand the cooperation of GATA2 with SMAD4 in promoting TGFβ1 and AR signaling and mediating inherited PCa risk and progression. RESULTS: In this study, by integrated genomics and experimental analysis, we identified GATA2 as a prevalent metastasis-associated genomic amplification to transcriptionally augment its own expression in PCa. Functional experiments demonstrated that GATA2 physically interacted and cooperated with SMAD4 for genome-wide chromatin co-occupancy and co-regulation of PCa genes and metastasis pathways like TGFβ signaling. Mechanistically, GATA2 was cooperative with SMAD4 to enhance TGFβ and AR signaling pathways, and activated the expression of TGFβ1 via directly binding to a distal enhancer of TGFβ1. Strinkingly, GATA2 and SMAD4 globally mediated inherited PCa risk and formed a transcriptional complex with HOXB13 at the PCa risk-associated rs339331/6q22 enhancer, leading to increased expression of the PCa susceptibility gene RFX6. CONCLUSIONS: Our study prioritizes causal genomic amplification genes with prognostic values in PCa and reveals the pivotal roles of GATA2 in transcriptionally activating the expression of its own and TGFβ1, thereby co-opting to TGFβ1/SMAD4 signaling and RFX6 at 6q22 to modulate PCa predisposition and progression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02745-7. BioMed Central 2023-08-08 /pmc/articles/PMC10408074/ /pubmed/37550764 http://dx.doi.org/10.1186/s13046-023-02745-7 Text en © The Author(s) 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Yang, Xiayun
Zhang, Qin
Li, Shuxuan
Devarajan, Raman
Luo, Binjie
Tan, Zenglai
Wang, Zixian
Giannareas, Nikolaos
Wenta, Tomasz
Ma, Wenlong
Li, Yuqing
Yang, Yuehong
Manninen, Aki
Wu, Song
Wei, Gong-Hong
GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression
title GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression
title_full GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression
title_fullStr GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression
title_full_unstemmed GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression
title_short GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression
title_sort gata2 co-opts tgfβ1/smad4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10408074/
https://www.ncbi.nlm.nih.gov/pubmed/37550764
http://dx.doi.org/10.1186/s13046-023-02745-7
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