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LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription

BACKGROUND: The majority of breast cancer patients die of metastasis rather than primary tumors, whereas the molecular mechanisms orchestrating cancer metastasis remains poorly understood. Long noncoding RNAs (lncRNA) have been shown to regulate cancer occurrence and progression. However, the lncRNA...

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Autores principales: Xiu, Bingqiu, Chi, Yayun, Liu, Lei, Chi, Weiru, Zhang, Qi, Chen, Jiajian, Guo, Rong, Si, Jing, Li, Lun, Xue, Jingyan, Shao, Zhi-Ming, Wu, Zhao-Hui, Huang, Shenglin, Wu, Jiong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921600/
https://www.ncbi.nlm.nih.gov/pubmed/31856843
http://dx.doi.org/10.1186/s12943-019-1115-y
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author Xiu, Bingqiu
Chi, Yayun
Liu, Lei
Chi, Weiru
Zhang, Qi
Chen, Jiajian
Guo, Rong
Si, Jing
Li, Lun
Xue, Jingyan
Shao, Zhi-Ming
Wu, Zhao-Hui
Huang, Shenglin
Wu, Jiong
author_facet Xiu, Bingqiu
Chi, Yayun
Liu, Lei
Chi, Weiru
Zhang, Qi
Chen, Jiajian
Guo, Rong
Si, Jing
Li, Lun
Xue, Jingyan
Shao, Zhi-Ming
Wu, Zhao-Hui
Huang, Shenglin
Wu, Jiong
author_sort Xiu, Bingqiu
collection PubMed
description BACKGROUND: The majority of breast cancer patients die of metastasis rather than primary tumors, whereas the molecular mechanisms orchestrating cancer metastasis remains poorly understood. Long noncoding RNAs (lncRNA) have been shown to regulate cancer occurrence and progression. However, the lncRNAs that drive metastasis in cancer patients and their underlying mechanisms are still largely unknown. METHODS: lncRNAs highly expressed in metastatic lymph nodes were identified by microarray. Survival analysis were made by Kaplan-Meier method. Cell proliferation, migration, and invasion assay was performed to confirm the phenotype of LINC02273. Tail vein model and mammary fat pad model were used for in vivo study. RNA pull-down and RIP assay were used to confirm the interaction of hnRNPL and LINC02273. Chromatin isolation by RNA purification followed by sequencing (ChIRP-seq), RNA-seq, ChIP-seq, and luciferase reporter assay reveal hnRNPL-LINC02273 regulates AGR2. Antisense oligonucleotides were used for in vivo treatment. RESULTS: We identified a novel long noncoding RNA LINC02273, whose expression was significantly elevated in metastatic lesions compared to the primary tumors, by genetic screen of matched tumor samples. Increased LINC02273 promoted breast cancer metastasis in vitro and in vivo. We further showed that LINC02273 was stabilized by hnRNPL, a protein increased in metastatic lesions, in breast cancer cells. Mechanistically, hnRNPL-LINC02273 formed a complex which activated AGR2 transcription and promoted cancer metastasis. The recruitment of hnRNPL-LINC02273 complex to AGR2 promoter region epigenetically upregulated AGR2 by augmenting local H3K4me3 and H3K27ac levels. Combination of AGR2 and LINC02273 was an independent prognostic factor for predicting breast cancer patient survival. Moreover, our data revealed that LINC02273-targeting antisense oligonucleotides (ASO) substantially inhibited breast cancer metastasis in vivo. CONCLUSIONS: Our findings uncover a key role of LINC02273-hnRNPL-AGR2 axis in breast cancer metastasis and provide potential novel therapeutic targets for metastatic breast cancer intervention.
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spelling pubmed-69216002019-12-30 LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription Xiu, Bingqiu Chi, Yayun Liu, Lei Chi, Weiru Zhang, Qi Chen, Jiajian Guo, Rong Si, Jing Li, Lun Xue, Jingyan Shao, Zhi-Ming Wu, Zhao-Hui Huang, Shenglin Wu, Jiong Mol Cancer Research BACKGROUND: The majority of breast cancer patients die of metastasis rather than primary tumors, whereas the molecular mechanisms orchestrating cancer metastasis remains poorly understood. Long noncoding RNAs (lncRNA) have been shown to regulate cancer occurrence and progression. However, the lncRNAs that drive metastasis in cancer patients and their underlying mechanisms are still largely unknown. METHODS: lncRNAs highly expressed in metastatic lymph nodes were identified by microarray. Survival analysis were made by Kaplan-Meier method. Cell proliferation, migration, and invasion assay was performed to confirm the phenotype of LINC02273. Tail vein model and mammary fat pad model were used for in vivo study. RNA pull-down and RIP assay were used to confirm the interaction of hnRNPL and LINC02273. Chromatin isolation by RNA purification followed by sequencing (ChIRP-seq), RNA-seq, ChIP-seq, and luciferase reporter assay reveal hnRNPL-LINC02273 regulates AGR2. Antisense oligonucleotides were used for in vivo treatment. RESULTS: We identified a novel long noncoding RNA LINC02273, whose expression was significantly elevated in metastatic lesions compared to the primary tumors, by genetic screen of matched tumor samples. Increased LINC02273 promoted breast cancer metastasis in vitro and in vivo. We further showed that LINC02273 was stabilized by hnRNPL, a protein increased in metastatic lesions, in breast cancer cells. Mechanistically, hnRNPL-LINC02273 formed a complex which activated AGR2 transcription and promoted cancer metastasis. The recruitment of hnRNPL-LINC02273 complex to AGR2 promoter region epigenetically upregulated AGR2 by augmenting local H3K4me3 and H3K27ac levels. Combination of AGR2 and LINC02273 was an independent prognostic factor for predicting breast cancer patient survival. Moreover, our data revealed that LINC02273-targeting antisense oligonucleotides (ASO) substantially inhibited breast cancer metastasis in vivo. CONCLUSIONS: Our findings uncover a key role of LINC02273-hnRNPL-AGR2 axis in breast cancer metastasis and provide potential novel therapeutic targets for metastatic breast cancer intervention. BioMed Central 2019-12-19 /pmc/articles/PMC6921600/ /pubmed/31856843 http://dx.doi.org/10.1186/s12943-019-1115-y Text en © The Author(s). 2019 Open Access This 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
Xiu, Bingqiu
Chi, Yayun
Liu, Lei
Chi, Weiru
Zhang, Qi
Chen, Jiajian
Guo, Rong
Si, Jing
Li, Lun
Xue, Jingyan
Shao, Zhi-Ming
Wu, Zhao-Hui
Huang, Shenglin
Wu, Jiong
LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
title LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
title_full LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
title_fullStr LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
title_full_unstemmed LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
title_short LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
title_sort linc02273 drives breast cancer metastasis by epigenetically increasing agr2 transcription
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921600/
https://www.ncbi.nlm.nih.gov/pubmed/31856843
http://dx.doi.org/10.1186/s12943-019-1115-y
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