Oncotarget

Research Papers:

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

Hanbing An, Sydney L. Stoops, Natasha G. Deane, Jing Zhu, Jinghuan Zi, Connie Weaver, Alex G. Waterson, Andries Zijlstra, Craig W. Lindsley and Robert Daniel Beauchamp _

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Oncotarget. 2015; 6:22934-22948. https://doi.org/10.18632/oncotarget.4473

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Abstract

Hanbing An1, Sydney L. Stoops2, Natasha G. Deane1,3, Jing Zhu1, Jinghuan Zi1, Connie Weaver1, Alex G. Waterson2,4, Andries Zijlstra5, Craig W. Lindsley2,4,6 and Robert Daniel Beauchamp1,2,7,8

1 Department of Surgery, Nashville, Tennessee, USA

2 Department of Pharmacology, Nashville, Tennessee, USA

3 Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA

4 Vanderbilt Institute of Chemical Biology, Nashville, Tennessee, USA

5 Department of Pathology, Microbiology and Immunology, Nashville, Tennessee, USA

6 Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee, USA

7 Department of Cancer Biology, Nashville, Tennessee, USA

8 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

Correspondence to:

Robert Daniel Beauchamp, email:

Keywords: small molecule, E-cadherin, EMT

Received: April 03, 2015 Accepted: May 27, 2015 Published: June 15, 2015

Abstract

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.


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