Role of the SMYD3 histone methyltransferase in tumorigenesis

Medjkane, Souhila; Cock-Rada, Alicia; Weitzman, Jonathan B

doi:10.4161/cc.20415

Cited by 15 publications

(8 citation statements)

References 9 publications

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“…This observation might seem contradictory to our results; however, we provided compelling evidence that SMYD3 has a bona fide stimulation effect on H3K4me3 and that this activity is critical for target gene expression in our assay system. Thus, once H4K5me3-specific antibodies are available, it will be important to determine whether H4K5me3 may impact on chromatin function at the global level whereas H3K4me3 effects are rather focused on specific genes, as recently proposed ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells

Kim

Schmidt

et al. 2015

Nucleic Acids Res

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SET and MYND domain containing protein 3 (SMYD3) is a histone methyltransferase, which has been implicated in cell growth and cancer pathogenesis. Increasing evidence suggests that SMYD3 can influence distinct oncogenic processes by acting as a gene-specific transcriptional regulator. However, the mechanistic aspects of SMYD3 transactivation and whether SMYD3 acts in concert with other transcription modulators remain unclear. Here, we show that SMYD3 interacts with the human positive coactivator 4 (PC4) and that such interaction potentiates a group of genes whose expression is linked to cell proliferation and invasion. SMYD3 cooperates functionally with PC4, because PC4 depletion results in the loss of SMYD3-mediated H3K4me3 and target gene expression. Individual depletion of SMYD3 and PC4 diminishes the recruitment of both SMYD3 and PC4, indicating that SMYD3 and PC4 localize at target genes in a mutually dependent manner. Artificial tethering of a SMYD3 mutant incapable of binding to its cognate elements and interacting with PC4 to target genes is sufficient for achieving an active transcriptional state in SMYD3-deficient cells. These observations suggest that PC4 contributes to SMYD3-mediated transactivation primarily by stabilizing SMYD3 occupancy at target genes. Together, these studies define expanded roles for SMYD3 and PC4 in gene regulation and provide an unprecedented documentation of their cooperative functions in stimulating oncogenic transcription.

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Section: Discussionmentioning

confidence: 99%

Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells

Kim

Schmidt

et al. 2015

Nucleic Acids Res

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“…SMYD1–3 methylate H3K4, which is a methylation site promoting active transcription [ 1 , 2 , 7 , 14 , 15 ]. However, SMYD does not have an effect on global H3K4 methylation but appears to impact selective promoter regions [ 16 , 17 ]. SMYD1 binds directly to class I and class II histone deacetylases (HDAC) and represses transcription from an SV40-luciferase reporter [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Structure and Function of SET and MYND Domain-Containing Proteins

Spellmon

Holcomb

Trescott

et al. 2015

IJMS

139

180

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SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control. During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle. SMYD proteins are also of therapeutic interest due to the growing list of carcinomas and cardiovascular diseases linked to SMYD overexpression or dysfunction making them a putative target for drug intervention. This review will examine the biological relevance and gather all of the current structural data of SMYD proteins.

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“…SETD1B catalyzes the methylation of H3K4, and several other enzymes including SETD1A, histone-lysine N-methyltransferase SETD7, MLL1-4 and histone-lysine N-methyltransferase SMYD (SMYD) 1–3 catalyze the same reaction (11). The level of H3K4 methylation affects gene transcription, but this level depends not only on the activity of these methyltransferases but also on that of demethylases, or ‘erasers’ (19). In humans, the erasers for H3K4me are lysine-specific histone demethylase (LSD)1-2, lysine-specific demethylase 5A-D and ribosomal oxygenase 1.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, the erasers for H3K4me are lysine-specific histone demethylase (LSD)1-2, lysine-specific demethylase 5A-D and ribosomal oxygenase 1. For example, a previous study described the role of the SMYD3 histone methyltransferase in tumorigenesis and whether the effects are local or global (19). JARID1B promotes metastasis and the epithelial-mesenchymal transition via phosphatase and tensin homolog/protein kinase B signaling in HCC cells (20).…”

Section: Discussionmentioning

confidence: 99%

High‑level SETD1B gene expression is associated with unfavorable prognosis in hepatocellular carcinoma

Chen

Wang

et al. 2019

Mol Med Report

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The SET domain-containing 1B (SETD1B) gene is involved in multiple biological processes, including tumor development and progression. However, the role of SETD1B in hepatocellular carcinoma (HCC) is largely unexplored. The present study, examined the expression of SETD1B in patients with HCC and assessed its clinical significance. Reverse transcriptase quantitative polymerase chain reaction and western blot analysis results revealed that the expression levels of SETD1B mRNA and protein were significantly increased in HCC tumor tissues compared with the adjacent normal tissues. In addition, an analysis of the patient clinical factors indicated that increased levels of SETD1B expression were associated with tumor size, clinical stage and liver cirrhosis. Patients with HCC with decreased levels of SETD1B expression exhibited longer survival times compared with those with increased levels of SETD1B expression. In addition, Cox's regression analysis results implied that the upregulation of SETD1B was an independent prognostic marker in patients with HCC. Taken together, the results demonstrated that SETD1B is essential in the progression of HCC and may be used as a potential prognostic marker and therapeutic target in HCC.

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Role of the SMYD3 histone methyltransferase in tumorigenesis

Cited by 15 publications

References 9 publications

Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells

Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells

Structure and Function of SET and MYND Domain-Containing Proteins

High‑level SETD1B gene expression is associated with unfavorable prognosis in hepatocellular carcinoma

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