Abstract
SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment.
Highlights
Lysine Methylation and CancerOver the past decades, several enzymes were identified as chromatin writers of epigenetic marks.Subsequently, novel classes of erasers of these marks have been characterized, as well as of chromatin readers, which translate these chromatin marks in a functional output [1].A number of studies and technological advances of recent years have improved our understanding of one of these histone marks, histone lysine methylation, emphasizing its fundamental role in chromatin processes, such as transcription, DNA replication and DNA repair, and revealed lysine methylation involvement in different cellular processes, such as cell fate determination and maintenance, cell signaling, genome stability and cell proliferation [2]
These insights have led to the elucidation of an extensive set of functions for lysine methylases (KMT) that can be associated with molecular events contributing to tumorigenesis, tumor maintenance and dissemination [3]
The colocalization of SMYD3 and H2A.Z.1K101me2 at the promoter of cyclin A1 promotes its expression and G1-S progression in breast carcinoma (BrCA) cells [41]. In agreement with these data, and with the SMYD3 role in regulating the cell cycle related gene, we have shown that SMYD3 is required for proper S phase completion in different types of tumor cells (CRC, lung, pancreatic, ovarian and prostate cancer)
Summary
Several enzymes were identified as chromatin writers of epigenetic marks. A number of studies and technological advances of recent years have improved our understanding of one of these histone marks, histone lysine methylation, emphasizing its fundamental role in chromatin processes, such as transcription, DNA replication and DNA repair, and revealed lysine methylation involvement in different cellular processes, such as cell fate determination and maintenance, cell signaling, genome stability and cell proliferation [2] These insights have led to the elucidation of an extensive set of functions for lysine methylases (KMT) that can be associated with molecular events contributing to tumorigenesis, tumor maintenance and dissemination [3].
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