Abstract 4097: Small molecule mediated transcriptional derepression of E-cadherin and inhibition of epithelial to mesenchymal transition
Authors: An Hanbing , Deane Natasha , Stoops Sydney , Zhu Jing , Waterson Alex , Zijlstra Andries , Lindsley Craig , Beauchamp Robert Daniel 
Published: August 2015

BACKGROUND: Transcriptional repression of E-Cadherin is a hallmark of Epithelial-to-Mesenchymal Transition (EMT) and is associated with metastasis in cancer. Understanding mechanisms behind E-cadherin repression may provide important insights into the regulation of EMT and novel therapeutic strategies for cancer. In this report, we applied a medicinal chemistry approach to generate a novel EMT-reversing compound, ML327. We tested the hypothesis that ML327 activity impinges directly on the mechanism of EMT in cancer and represents a potential therapeutic agent to block or reverse EMT in vivo.

METHODOLOGY/PRINCIPAL FINDINGS: We used cell based biochemical approaches to show that ML327 increases E-cadherin expression in 5 cancer cell lines and 2 non-transformed cell lines. ML327 was shown to induce global changes in histone modifications, but through a distinct mechanism than similar chemical agents such as Histone De-Acetylase (HDAC) inhibitors. Cell based assays were used to show that ML327 inhibits cell invasion, partially reverses EMT, and inhibits metastasis in vivo. We examined gene expression changes induced by ML327 within 3 hrs in the presence of cycloheximide by RNA-seq and determined a mechanistic requirement for Hepatocyte Nuclear Factor 4α (HNF4α) in ML327 activity on E-cadherin gene expression. Through direct testing, we have determined the ML327 is not a promiscuous chemical probe and that it lacks direct HDAC inhibitory and kinase inhibitory activity, however, our study is limited by the lack of identification of the direct cellular target. Significant ongoing studies are designed to address this limitation.

CONCLUSIONS/SIGNIFICANCE: ML327 increases E-cadherin in cells and translate to an important biological behavior in vivo that may be exploited for therapeutic potential in cancer. Furthermore, ML327 represents a novel chemical structure for continued pharmacological optimization toward the development of novel therapeutics. ACKNOWLEDGEMENTS: This work was supported by NIH through the Molecular Library Probe Center Network (MPLCN) under grant U54MH084659 to CWL.

DISCLOSURE of POTENTIAL CONFLICT of INTEREST: No potential conflicts of interest were disclosed.

DISCLOSURE of CHEMICAL STRUCTURES: Chemical compounds were used in this scientific work to generate the data, and the structures of the compounds will be disclosed at the time of presentation at the meeting.

Citation Format: Hanbing An, Natasha Deane, Sydney Stoops, Jing Zhu, Alex Waterson, Andries Zijlstra, Craig Lindsley, Robert Daniel Beauchamp. Small molecule mediated transcriptional derepression of E-cadherin and inhibition of epithelial to mesenchymal transition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4097. doi:10.1158/1538-7445.AM2015-4097