Research Papers:

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

Mark A. Brown _, Kenneth Foreman, June Harriss, Chhaya Das, Li Zhu, Melissa Edwards, Salam Shaaban and Haley Tucker

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Oncotarget. 2015; 6:4005-4019. https://doi.org/10.18632/oncotarget.2970

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Mark A. Brown1,*, Kenneth Foreman2,*, June Harriss3, Chhaya Das3, Li Zhu3, Melissa Edwards1,3, Salam Shaaban4, Haley Tucker3

1Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA

2Coferon Inc., Stony Brook, NY 11791, USA

3University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA

4Abbvie, Worcester, MA 01605, USA

*These authors have contributed equally to this work

Correspondence to:

Haley Tucker, e-mail: [email protected]

Keywords: HSP90, SMYD3, tumorigenesis, lysine methylation, histone modifications

Received: August 08, 2014     Accepted: December 16, 2014     Published: March 02, 2015


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.

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