C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis.
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.
Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
Mark A
MA
Brown
Coferon Inc., Stony Brook, NY 11791, USA.
Kenneth
K
Foreman
University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA.
June
J
Harriss
University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA.
Chhaya
C
Das
University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA.
Li
L
Zhu
Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA.|University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA.
Melissa
M
Edwards
Abbvie, Worcester, MA 01605, USA.
Salam
S
Shaaban
University of Texas at Austin, Institute of Cellular and Molecular Biology, Austin, TX 78712, USA.
Haley
H
Tucker
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014162:Transfection
D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human