Cargando…

Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition

Transcriptional repression of E-cadherin is a hallmark of Epithelial-to-Mesenchymal Transition (EMT) and is associated with cancer cell invasion and metastasis. Understanding the mechanisms underlying E-cadherin repression during EMT may provide insights into the development of novel targeted therap...

Descripción completa

Detalles Bibliográficos
Autores principales: An, Hanbing, Stoops, Sydney L., Deane, Natasha G., Zhu, Jing, Zi, Jinghuan, Weaver, Connie, Waterson, Alex G., Zijlstra, Andries, Lindsley, Craig W., Beauchamp, Robert Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673210/
https://www.ncbi.nlm.nih.gov/pubmed/26082441
_version_ 1782404691243565056
author An, Hanbing
Stoops, Sydney L.
Deane, Natasha G.
Zhu, Jing
Zi, Jinghuan
Weaver, Connie
Waterson, Alex G.
Zijlstra, Andries
Lindsley, Craig W.
Beauchamp, Robert Daniel
author_facet An, Hanbing
Stoops, Sydney L.
Deane, Natasha G.
Zhu, Jing
Zi, Jinghuan
Weaver, Connie
Waterson, Alex G.
Zijlstra, Andries
Lindsley, Craig W.
Beauchamp, Robert Daniel
author_sort An, Hanbing
collection PubMed
description Transcriptional repression of E-cadherin is a hallmark of Epithelial-to-Mesenchymal Transition (EMT) and is associated with cancer cell invasion and metastasis. Understanding the mechanisms underlying E-cadherin repression during EMT may provide insights into the development of novel targeted therapeutics for cancer. Here, we report on the chemical probe, ML327, which de-represses E-cadherin transcription, partially reverses EMT, and inhibits cancer cell invasiveness and tumor cell migration in vitro and in vivo. Induction of E-cadherin mRNA expression by ML327 treatment does not require de novo protein synthesis. RNA sequencing analysis revealed that ML327 treatment significantly alters expression of over 2,500 genes within three hours in the presence of the translational inhibitor, cycloheximide. Network analysis reveals Hepatocyte Nuclear Factor 4-alpha (HNF4α) as the most significant upstream transcriptional regulator of multiple genes whose expressions were altered by ML327 treatment. Further, small interfering RNA-mediated depletion of HNF4α markedly attenuates the E-cadherin expression response to ML327. In summary, ML327 represents a valuable tool to understand mechanisms of EMT and may provide the basis for a novel targeted therapeutic strategy for carcinomas.
format Online
Article
Text
id pubmed-4673210
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-46732102015-12-23 Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition An, Hanbing Stoops, Sydney L. Deane, Natasha G. Zhu, Jing Zi, Jinghuan Weaver, Connie Waterson, Alex G. Zijlstra, Andries Lindsley, Craig W. Beauchamp, Robert Daniel Oncotarget Research Paper Transcriptional repression of E-cadherin is a hallmark of Epithelial-to-Mesenchymal Transition (EMT) and is associated with cancer cell invasion and metastasis. Understanding the mechanisms underlying E-cadherin repression during EMT may provide insights into the development of novel targeted therapeutics for cancer. Here, we report on the chemical probe, ML327, which de-represses E-cadherin transcription, partially reverses EMT, and inhibits cancer cell invasiveness and tumor cell migration in vitro and in vivo. Induction of E-cadherin mRNA expression by ML327 treatment does not require de novo protein synthesis. RNA sequencing analysis revealed that ML327 treatment significantly alters expression of over 2,500 genes within three hours in the presence of the translational inhibitor, cycloheximide. Network analysis reveals Hepatocyte Nuclear Factor 4-alpha (HNF4α) as the most significant upstream transcriptional regulator of multiple genes whose expressions were altered by ML327 treatment. Further, small interfering RNA-mediated depletion of HNF4α markedly attenuates the E-cadherin expression response to ML327. In summary, ML327 represents a valuable tool to understand mechanisms of EMT and may provide the basis for a novel targeted therapeutic strategy for carcinomas. Impact Journals LLC 2015-06-10 /pmc/articles/PMC4673210/ /pubmed/26082441 Text en Copyright: © 2015 An et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
An, Hanbing
Stoops, Sydney L.
Deane, Natasha G.
Zhu, Jing
Zi, Jinghuan
Weaver, Connie
Waterson, Alex G.
Zijlstra, Andries
Lindsley, Craig W.
Beauchamp, Robert Daniel
Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition
title Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition
title_full Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition
title_fullStr Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition
title_full_unstemmed Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition
title_short Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition
title_sort small molecule/ml327 mediated transcriptional de-repression of e-cadherin and inhibition of epithelial-to-mesenchymal transition
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673210/
https://www.ncbi.nlm.nih.gov/pubmed/26082441
work_keys_str_mv AT anhanbing smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT stoopssydneyl smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT deanenatashag smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT zhujing smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT zijinghuan smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT weaverconnie smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT watersonalexg smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT zijlstraandries smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT lindsleycraigw smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition
AT beauchamprobertdaniel smallmoleculeml327mediatedtranscriptionalderepressionofecadherinandinhibitionofepithelialtomesenchymaltransition