Abstract LB-187: Novel mechanistic insights into the bioactive compound honokiol-mediated inhibition of epithelial to mesenchymal transition in breast cancer: Therapeutic modulation of miR-34a via tumor suppressor LKB1
Authors: Avtanski Dimiter B. , Bonner Michael Y. , Tiutan Timothy P. , Arbiser Jack L. , Saxena Neeraj K. , Sharma Dipali 
Published: May 2015

Abstract
Introduction: An emerging hypothesis is that epithelial-mesenchymal-transition (EMT) bestows metastatic potential to epithelial cancer cells enabling them to invade, migrate and subsequently disseminate to form distant metastases resulting in non-curable disease. Pharmacological inhibition of EMT can potentially lead to reversion of aggressive breast cancer cells to a more-differentiated epithelial phenotype by inducing mesenchymal-epithelial transition (MET) to prevent metastasis and diminish distant recurrence. The importance of active constitutive agents in natural products has become increasingly apparent owing to their potential cancer chemopreventive and therapeutic properties. Honokiol (HNK) is a natural phenolic compound isolated from an extract of seed cones from Magnolia grandiflora. Recent studies from our lab demonstrated that HNK has suppressing effects on different aspects of cancer progression. The present study was designed to specifically examine the potential of HNK to inhibit EMT and elucidate the molecular mechanism by which HNK inhibits EMT in breast cancer cells.
Aim: To elucidate the mechanism by which HNK inhibits EMT in breast cancer cells.
Results: Here, we provide molecular evidence that HNK inhibits EMT in breast cancer cells resulting in significant downregulation of mesenchymal marker proteins and concurrent upregulation of epithelial markers. In vitro and in vivo analyses show functional interactions between HNK, STAT3, and EMT-signaling components. Mechanistically, HNK inhibits recruitment of STAT3 on mesenchymal transcription factor ZEB1 promoter resulting in decreased ZEB1 expression and nuclear translocation. We also discover that HNK increases E-cadherin expression via STAT3-mediated release of ZEB1 from E-cadherin promoter. Since ZEB1 is a transcriptional repressor of miR-34a, we next examined the effect of HNK on miR-34a expression. Intriguingly, we found that HNK upregulates the levels of miR-34a in a time- and dose-dependent manner. It is interesting to note that HNK treatment also increases the expression of upstream kinase and tumor suppressor LKB1. Utilizing LKB1-null cells and gain-of-function strategies, we found that HNK-mediated increase in miR-34a is regulated by tumor suppressor LKB1.
Conclusions: Taken together, these studies provide evidence for a previously unrecognized cross-talk between HNK and miR-34a via tumor suppressor LKB1 in inhibiting EMT in breast cancer.
Citation Format: Dimiter B. Avtanski, Michael Y. Bonner, Timothy P. Tiutan, Jack L. Arbiser, Neeraj K. Saxena, Dipali Sharma. Novel mechanistic insights into the bioactive compound honokiol-mediated inhibition of epithelial to mesenchymal transition in breast cancer: Therapeutic modulation of miR-34a via tumor suppressor LKB1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-187. doi:10.1158/1538-7445.AM2014-LB-187