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

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.

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

“…The remaining part of the SET (aa94-242) follows the MYND domain and it is formed by an intermediate or linker region (I-SET) and the C-SET domain, which contains key residues for the catalytic activity ( Figure 1). In SMYD3, the TPR-like domain (aa271-428) appears to modulate the association with the MEEVD peptide within HSP90 and likely many other proteins [10,14]. The HSP90 interaction In SMYD3, the TPR-like domain (aa271-428) appears to modulate the association with the MEEVD peptide within HSP90 and likely many other proteins [10,14].…”

“…In SMYD3, the TPR-like domain (aa271-428) appears to modulate the association with the MEEVD peptide within HSP90 and likely many other proteins [10,14]. The HSP90 interaction In SMYD3, the TPR-like domain (aa271-428) appears to modulate the association with the MEEVD peptide within HSP90 and likely many other proteins [10,14]. The HSP90 interaction positively regulates SMYD3 in vitro methylation activity, and point mutations in residues that are crucial for HSP90 association affect SMYD3 cellular compartmentalization ( Figure 1) [14].…”

“…Positive correlation with HCC development [18] Human cancer Lung Shorter progression free survival [22] Human cancer Liver Shorter overall and progression free survival [22] Human cancer ESCC, ovarian, colon, glioma Shorter overall survival [22,25,56,59,88] This hypothesis is supported by different studies where SMYD3 has been found to interact with factors belonging to complexes that influence proliferative pathways, in cancer cell extracts. For instance, SMYD3 associates with the heat shock protein 90 (HSP90) and loss of this interaction results in impairment of the ability of SMYD3 to bind to the chromatin and to promote cell proliferation [14]. The PC4 coactivator is another component of the transcriptional machinery that interacts with SMYD3, stabilizing its chromatin occupancy and promoting the activation of cell proliferation and invasion.…”

New open conformation of SMYD3 implicates conformational selection and allostery

“…SMYD3 in vitro activity can be enhanced by Hsp90 and DNA binding [2,18]. The Hsp90 binding site has been mapped to a TPR-like C-terminal domain (CTD) [19]. Due to the closed conformation, the predicted Hsp90 binding site is half-buried and therefore the question remains how Hsp90 binds to SMYD3 and enhances its activity.…”

Characterization of the SMYD Family of Lysine Methyltransferases: Reflections upon Key Findings and Therapeutic Implications

“…Further potential for therapeutic applications associated with SMYD3 are manifest in the recent findings that a degenerate tetratricopeptide repeat (TPR)-like domain encoded in the SMYD3 Cterminal domain (CTD) mediates physical interaction with the nuclear chaperone, HSP90 23 . In the same study, it is further demonstrated that the CTD of SMYD3 is essential for its basal HMTase activity and that the TPR-like structure facilitates HSP90-enhanced catalysis.…”