Cargando…

The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells

The epigenetic reader, bromodomain-containing 4 (BRD4), is overexpressed in hepatocellular carcinoma (HCC), and BRD4 inhibition is considered as a new therapeutic approach. The BRD inhibitor JQ1 is known to inhibit the enrichment of BRD4 at enhancer sites. Gene network analyses have implicated long...

Descripción completa

Detalles Bibliográficos
Autores principales: Choi, Hae In, An, Ga Yeong, Yoo, Eunyoung, Baek, Mina, Binas, Bert, Chai, Jin Choul, Lee, Young Seek, Jung, Kyoung Hwa, Chai, Young Gyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095596/
https://www.ncbi.nlm.nih.gov/pubmed/35546353
http://dx.doi.org/10.1038/s41598-022-11868-4
_version_ 1784705790271029248
author Choi, Hae In
An, Ga Yeong
Yoo, Eunyoung
Baek, Mina
Binas, Bert
Chai, Jin Choul
Lee, Young Seek
Jung, Kyoung Hwa
Chai, Young Gyu
author_facet Choi, Hae In
An, Ga Yeong
Yoo, Eunyoung
Baek, Mina
Binas, Bert
Chai, Jin Choul
Lee, Young Seek
Jung, Kyoung Hwa
Chai, Young Gyu
author_sort Choi, Hae In
collection PubMed
description The epigenetic reader, bromodomain-containing 4 (BRD4), is overexpressed in hepatocellular carcinoma (HCC), and BRD4 inhibition is considered as a new therapeutic approach. The BRD inhibitor JQ1 is known to inhibit the enrichment of BRD4 at enhancer sites. Gene network analyses have implicated long non-coding RNAs (lncRNAs) in the effects of JQ1, but the precise molecular events remain unexplored. Here, we report that in HepG2 cells, JQ1 significantly reduced various proliferation-related lncRNAs, but up-regulated the known liver tumor marker, MALAT1. Using ChIP-sequencing data, ChIP-qPCR, luciferase reporter assays, and chromatin conformation capture (3C), we characterized the MALAT1 gene locus. We found that JQ1 elicited a rearrangement of its chromatin looping conformation, which involved the putative enhancers E1, E2, E3, the gene body, and the promoter. We further found that the forkhead box protein A2 (FOXA2) binds to E2 and the promoter; suppression of FOXA2 expression resulted in MALAT1 up-regulation and increased cell proliferation. These results suggest that the inhibition of MALAT1 may improve the effect of BET inhibitors as an anti-cancer therapy and that FOXA2 would be a suitable target for that approach.
format Online
Article
Text
id pubmed-9095596
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-90955962022-05-13 The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells Choi, Hae In An, Ga Yeong Yoo, Eunyoung Baek, Mina Binas, Bert Chai, Jin Choul Lee, Young Seek Jung, Kyoung Hwa Chai, Young Gyu Sci Rep Article The epigenetic reader, bromodomain-containing 4 (BRD4), is overexpressed in hepatocellular carcinoma (HCC), and BRD4 inhibition is considered as a new therapeutic approach. The BRD inhibitor JQ1 is known to inhibit the enrichment of BRD4 at enhancer sites. Gene network analyses have implicated long non-coding RNAs (lncRNAs) in the effects of JQ1, but the precise molecular events remain unexplored. Here, we report that in HepG2 cells, JQ1 significantly reduced various proliferation-related lncRNAs, but up-regulated the known liver tumor marker, MALAT1. Using ChIP-sequencing data, ChIP-qPCR, luciferase reporter assays, and chromatin conformation capture (3C), we characterized the MALAT1 gene locus. We found that JQ1 elicited a rearrangement of its chromatin looping conformation, which involved the putative enhancers E1, E2, E3, the gene body, and the promoter. We further found that the forkhead box protein A2 (FOXA2) binds to E2 and the promoter; suppression of FOXA2 expression resulted in MALAT1 up-regulation and increased cell proliferation. These results suggest that the inhibition of MALAT1 may improve the effect of BET inhibitors as an anti-cancer therapy and that FOXA2 would be a suitable target for that approach. Nature Publishing Group UK 2022-05-11 /pmc/articles/PMC9095596/ /pubmed/35546353 http://dx.doi.org/10.1038/s41598-022-11868-4 Text en © The Author(s) 2022 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/) .
spellingShingle Article
Choi, Hae In
An, Ga Yeong
Yoo, Eunyoung
Baek, Mina
Binas, Bert
Chai, Jin Choul
Lee, Young Seek
Jung, Kyoung Hwa
Chai, Young Gyu
The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells
title The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells
title_full The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells
title_fullStr The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells
title_full_unstemmed The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells
title_short The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells
title_sort bromodomain inhibitor jq1 up-regulates the long non-coding rna malat1 in cultured human hepatic carcinoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095596/
https://www.ncbi.nlm.nih.gov/pubmed/35546353
http://dx.doi.org/10.1038/s41598-022-11868-4
work_keys_str_mv AT choihaein thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT angayeong thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT yooeunyoung thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT baekmina thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT binasbert thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT chaijinchoul thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT leeyoungseek thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT jungkyounghwa thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT chaiyounggyu thebromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT choihaein bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT angayeong bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT yooeunyoung bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT baekmina bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT binasbert bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT chaijinchoul bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT leeyoungseek bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT jungkyounghwa bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells
AT chaiyounggyu bromodomaininhibitorjq1upregulatesthelongnoncodingrnamalat1inculturedhumanhepaticcarcinomacells