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Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA...

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Autores principales: Ailiken, Guzhanuer, Kitamura, Kouichi, Hoshino, Tyuji, Satoh, Mamoru, Tanaka, Nobuko, Minamoto, Toshinari, Rahmutulla, Bahityar, Kobayashi, Sohei, Kano, Masayuki, Tanaka, Tomoaki, Kaneda, Atsushi, Nomura, Fumio, Matsubara, Hisahiro, Matsushita, Kazuyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028737/
https://www.ncbi.nlm.nih.gov/pubmed/32071290
http://dx.doi.org/10.1038/s41389-020-0205-4
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author Ailiken, Guzhanuer
Kitamura, Kouichi
Hoshino, Tyuji
Satoh, Mamoru
Tanaka, Nobuko
Minamoto, Toshinari
Rahmutulla, Bahityar
Kobayashi, Sohei
Kano, Masayuki
Tanaka, Tomoaki
Kaneda, Atsushi
Nomura, Fumio
Matsubara, Hisahiro
Matsushita, Kazuyuki
author_facet Ailiken, Guzhanuer
Kitamura, Kouichi
Hoshino, Tyuji
Satoh, Mamoru
Tanaka, Nobuko
Minamoto, Toshinari
Rahmutulla, Bahityar
Kobayashi, Sohei
Kano, Masayuki
Tanaka, Tomoaki
Kaneda, Atsushi
Nomura, Fumio
Matsubara, Hisahiro
Matsushita, Kazuyuki
author_sort Ailiken, Guzhanuer
collection PubMed
description Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR(−/−)) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR(+/) mice (K19-Wnt1/C2mE x FIR(+/−)). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR(+/−) mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers.
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spelling pubmed-70287372020-03-04 Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer Ailiken, Guzhanuer Kitamura, Kouichi Hoshino, Tyuji Satoh, Mamoru Tanaka, Nobuko Minamoto, Toshinari Rahmutulla, Bahityar Kobayashi, Sohei Kano, Masayuki Tanaka, Tomoaki Kaneda, Atsushi Nomura, Fumio Matsubara, Hisahiro Matsushita, Kazuyuki Oncogenesis Article Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR(−/−)) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR(+/) mice (K19-Wnt1/C2mE x FIR(+/−)). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR(+/−) mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers. Nature Publishing Group UK 2020-02-18 /pmc/articles/PMC7028737/ /pubmed/32071290 http://dx.doi.org/10.1038/s41389-020-0205-4 Text en © The Author(s) 2020 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/.
spellingShingle Article
Ailiken, Guzhanuer
Kitamura, Kouichi
Hoshino, Tyuji
Satoh, Mamoru
Tanaka, Nobuko
Minamoto, Toshinari
Rahmutulla, Bahityar
Kobayashi, Sohei
Kano, Masayuki
Tanaka, Tomoaki
Kaneda, Atsushi
Nomura, Fumio
Matsubara, Hisahiro
Matsushita, Kazuyuki
Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer
title Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer
title_full Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer
title_fullStr Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer
title_full_unstemmed Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer
title_short Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer
title_sort post-transcriptional regulation of brg1 by firδexon2 in gastric cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028737/
https://www.ncbi.nlm.nih.gov/pubmed/32071290
http://dx.doi.org/10.1038/s41389-020-0205-4
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