Cordycepin (3′-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b

// Pu Zhang 1, 4 , Changjin Huang 2, 5 , Changliang Fu 4 , Yang Tian 2, 6 , Yijuan Hu 8 , Bochu Wang 3 , Amy Strasner 7 , Yang Song 1 , Erqun Song 1 1 Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China 2 Institute of Pathology, Third Military Medical University, Chongqing 400038, China 3 College of Bioengineering, Chongqing University, Chongqing 400030, China 4 Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA 5 Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA 6 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA 7 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA 8 Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA Correspondence to: Pu Zhang, e-mail: pxz122@swu.edu.cn ; e-mail: pxz122@gmail.com Keywords: cordycepin, miR-33b, metastasis, cell migration, focal adhesion Received: January 20, 2015      Accepted: February 14, 2015      Published: March 13, 2015 ABSTRACT Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Cordycepin, the active component of Cordyceps spp., has been identified to have anti-metastatic effect on tumor progression and thus possesses pharmacological and therapeutic potentials. However, the mechanisms of anti-metastatic effects of cordycepin at cellular levels remain elusive. We analyzed the effect of cordycepin on human melanoma miRNA expression profiles by miRNAarray and found that miR-33b was upregulated in highly-metastatic melanoma cell lines following cordycepin exposure. Cordycepin-mediated miR-33b expression was dependent on LXR-RXR heterodimer activation. miR-33b directly binds to HMGA2, Twist1 and ZEB1 3’-UTR to suppress their expression. The negative correlations between miR-33b levels and HMGA2, Twist1 or ZEB1 expression were detected in 72 patient melanoma tissue samples. By targeting HMGA2 and Twist1, miR-33b attenuated melanoma migration and invasiveness upon cordycepin exposure. miR-33b knockdown or ZEB1 overexpression reverted cordycepin-mediated mesenchymal-epithelial transition (MET), triggering the expression of N-cadherin. In spontaneous metastasis models, cordycepin suppressed tumor metastasis without altering primary tumor growth. We showed for the first time that targeting miRNA by cordycepin indicates a new mechanism of cordycepin-induced suppression of tumor metastasis and miR-33b/HMGA2/Twist1/ZEB1 axis plays critical roles in regulating melanoma dissemination.