2. Academic Validation
  3. Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition

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

  • Oncotarget. 2015 Sep 8;6(26):22934-48. doi: 10.18632/oncotarget.4473.
Hanbing An 1,  Sydney L Stoops 2,  Natasha G Deane 1 3,  Jing Zhu 1,  Jinghuan Zi 1,  Connie Weaver 1,  Alex G Waterson 2 4,  Andries Zijlstra 5,  Craig W Lindsley 2 4 6,  Robert Daniel Beauchamp 1 2 7 8
Affiliations

Affiliations

  • 1 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 2 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 3 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 4 Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 5 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 6 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 7 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 8 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
PMID: 26082441 DOI: 10.18632/oncotarget.4473
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.

Keywords

E-cadherin; EMT; small molecule.

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