C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis

// Mark A. Brown 1, * , Kenneth Foreman 2, * , June Harriss 3 , Chhaya Das 3 , Li Zhu 3 , Melissa Edwards 1, 3 , Salam Shaaban 4 , Haley Tucker 3 1 Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA 2 Coferon Inc., Stony Brook, NY 11791, USA 3 University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA 4 Abbvie, Worcester, MA 01605, USA * These authors have contributed equally to this work Correspondence to: Haley Tucker, e-mail: haleytucker@austin.utexas.edu Keywords: HSP90, SMYD3, tumorigenesis, lysine methylation, histone modifications Received: August 08, 2014      Accepted: December 16, 2014      Published: March 02, 2015 ABSTRACT The SMYD3 histone methyl transferase (HMTase) and the nuclear chaperone, HSP90, have been independently implicated as proto-oncogenes in several human malignancies. We show that a degenerate tetratricopeptide repeat (TPR)-like domain encoded in the SMYD3 C-terminal domain (CTD) mediates physical interaction with HSP90. We further demonstrate that the CTD of SMYD3 is essential for its basal HMTase activity and that the TPR-like structure is required for HSP90-enhanced enzyme activity. Loss of SMYD3-HSP90 interaction leads to SMYD3 mislocalization within the nucleus, thereby losing its chromatin association. This results in reduction of SMYD3-mediated cell proliferation and, potentially, impairment of SMYD3’s oncogenic activity. These results suggest a novel approach for blocking HSP90-driven malignancy in SMYD3-overexpressing cells with a reduced toxicity profile over current HSP90 inhibitors.