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PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression

The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional r...

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Autores principales: Liu, Ming, Yao, Bing, Gui, Tao, Guo, Chan, Wu, Xiaobin, Li, Jiahuang, Ma, Lingling, Deng, Yexuan, Xu, Peipei, Wang, Ying, Yang, Dongjun, Li, Qixiang, Zeng, Xiangwei, Li, Xinyu, Hu, Ruifeng, Ge, Jingru, Yu, Zenong, Chen, Yugen, Chen, Bing, Ju, Junyi, Zhao, Quan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150477/
https://www.ncbi.nlm.nih.gov/pubmed/32292506
http://dx.doi.org/10.7150/thno.42047
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author Liu, Ming
Yao, Bing
Gui, Tao
Guo, Chan
Wu, Xiaobin
Li, Jiahuang
Ma, Lingling
Deng, Yexuan
Xu, Peipei
Wang, Ying
Yang, Dongjun
Li, Qixiang
Zeng, Xiangwei
Li, Xinyu
Hu, Ruifeng
Ge, Jingru
Yu, Zenong
Chen, Yugen
Chen, Bing
Ju, Junyi
Zhao, Quan
author_facet Liu, Ming
Yao, Bing
Gui, Tao
Guo, Chan
Wu, Xiaobin
Li, Jiahuang
Ma, Lingling
Deng, Yexuan
Xu, Peipei
Wang, Ying
Yang, Dongjun
Li, Qixiang
Zeng, Xiangwei
Li, Xinyu
Hu, Ruifeng
Ge, Jingru
Yu, Zenong
Chen, Yugen
Chen, Bing
Ju, Junyi
Zhao, Quan
author_sort Liu, Ming
collection PubMed
description The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional repression of c-Myc target genes in gastric cancer. Methods: Immunohistochemistry was used to evaluate the expression of PRMT5, c-Myc and target genes in gastric cancer patients. PRMT5 and c-Myc interaction was assessed by immunofluorescence, co-immunoprecipitation and GST pull-down assays. Bioinformatics analysis, immunoblotting, real-time PCR, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Results: We found that c-Myc directly interacts with protein arginine methyltransferase 5 (PRMT5) to transcriptionally repress the expression of a cohort of genes, including PTEN, CDKN2C (p18(INK4C)), CDKN1A (p21(CIP1/WAF1)), CDKN1C (p57(KIP2)) and p63, to promote gastric cancer cell growth. Specifically, we found that PRMT5 was required to promote gastric cancer cell growth in vitro and in vivo, and for transcriptional repression of this cohort of genes, which was dependent on its methyltransferase activity. Consistently, the promoters of this gene cohort were enriched for both PRMT5-mediated symmetric di-methylation of histone H4 on Arg 3 (H4R3me2s) and c-Myc, and c-Myc depletion also upregulated their expression. H4R3me2s also colocalized with the c-Myc-binding E-box motif (CANNTG) on these genes. We show that PRMT5 directly binds to c-Myc, and this binding is required for transcriptional repression of the target genes. Both c-Myc and PRMT5 expression levels were upregulated in primary human gastric cancer tissues, and their expression levels inversely correlated with clinical outcomes. Conclusions: Taken together, our study reveals a novel mechanism by which PRMT5-dependent transcriptional repression of c-Myc target genes is required for gastric cancer progression, and provides a potential new strategy for therapeutic targeting of gastric cancer.
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spelling pubmed-71504772020-04-14 PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression Liu, Ming Yao, Bing Gui, Tao Guo, Chan Wu, Xiaobin Li, Jiahuang Ma, Lingling Deng, Yexuan Xu, Peipei Wang, Ying Yang, Dongjun Li, Qixiang Zeng, Xiangwei Li, Xinyu Hu, Ruifeng Ge, Jingru Yu, Zenong Chen, Yugen Chen, Bing Ju, Junyi Zhao, Quan Theranostics Research Paper The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional repression of c-Myc target genes in gastric cancer. Methods: Immunohistochemistry was used to evaluate the expression of PRMT5, c-Myc and target genes in gastric cancer patients. PRMT5 and c-Myc interaction was assessed by immunofluorescence, co-immunoprecipitation and GST pull-down assays. Bioinformatics analysis, immunoblotting, real-time PCR, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Results: We found that c-Myc directly interacts with protein arginine methyltransferase 5 (PRMT5) to transcriptionally repress the expression of a cohort of genes, including PTEN, CDKN2C (p18(INK4C)), CDKN1A (p21(CIP1/WAF1)), CDKN1C (p57(KIP2)) and p63, to promote gastric cancer cell growth. Specifically, we found that PRMT5 was required to promote gastric cancer cell growth in vitro and in vivo, and for transcriptional repression of this cohort of genes, which was dependent on its methyltransferase activity. Consistently, the promoters of this gene cohort were enriched for both PRMT5-mediated symmetric di-methylation of histone H4 on Arg 3 (H4R3me2s) and c-Myc, and c-Myc depletion also upregulated their expression. H4R3me2s also colocalized with the c-Myc-binding E-box motif (CANNTG) on these genes. We show that PRMT5 directly binds to c-Myc, and this binding is required for transcriptional repression of the target genes. Both c-Myc and PRMT5 expression levels were upregulated in primary human gastric cancer tissues, and their expression levels inversely correlated with clinical outcomes. Conclusions: Taken together, our study reveals a novel mechanism by which PRMT5-dependent transcriptional repression of c-Myc target genes is required for gastric cancer progression, and provides a potential new strategy for therapeutic targeting of gastric cancer. Ivyspring International Publisher 2020-03-15 /pmc/articles/PMC7150477/ /pubmed/32292506 http://dx.doi.org/10.7150/thno.42047 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Liu, Ming
Yao, Bing
Gui, Tao
Guo, Chan
Wu, Xiaobin
Li, Jiahuang
Ma, Lingling
Deng, Yexuan
Xu, Peipei
Wang, Ying
Yang, Dongjun
Li, Qixiang
Zeng, Xiangwei
Li, Xinyu
Hu, Ruifeng
Ge, Jingru
Yu, Zenong
Chen, Yugen
Chen, Bing
Ju, Junyi
Zhao, Quan
PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression
title PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression
title_full PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression
title_fullStr PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression
title_full_unstemmed PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression
title_short PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression
title_sort prmt5-dependent transcriptional repression of c-myc target genes promotes gastric cancer progression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150477/
https://www.ncbi.nlm.nih.gov/pubmed/32292506
http://dx.doi.org/10.7150/thno.42047
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