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Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells
Jin-Man Kim1, Kyunghwan Kim2, Thomas Schmidt3
1Department of Biochemistry and Molecular Biology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
Abstract:
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.
Insights
SET and MYND domain containing protein 3 (SMYD3) interacts with positive coactivator 4 (PC4) to promote gene expression linked to cancer cell proliferation and invasion. This interaction is crucial for SMYD3
Area of Science:
- Epigenetics and Gene Regulation
- Cancer Biology and Molecular Oncology
Background:
- SET and MYND domain containing protein 3 (SMYD3) is a histone methyltransferase involved in cell growth and cancer.
- SMYD3 functions as a gene-specific transcriptional regulator in oncogenic processes.
- The precise mechanisms of SMYD3 transactivation and its co-regulators are not fully understood.
Purpose of the Study:
- To investigate the interaction between SMYD3 and positive coactivator 4 (PC4).
- To elucidate the functional cooperation between SMYD3 and PC4 in gene regulation.
- To define the roles of SMYD3 and PC4 in promoting oncogenic transcription.
Main Methods:
- Co-immunoprecipitation assays to detect SMYD3-PC4 interaction.
- Depletion studies (siRNA) to assess the functional impact of SMYD3 and PC4.
- Chromatin immunoprecipitation (ChIP) to analyze H3K4me3 modification and protein recruitment.
- Reporter gene assays and gene expression analysis to quantify transcriptional activity.
Main Results:
- SMYD3 directly interacts with PC4, enhancing the expression of genes associated with cell proliferation and invasion.
- PC4 depletion abrogates SMYD3-mediated H3K4me3 modification and target gene expression.
- SMYD3 and PC4 exhibit mutual dependence for their localization at target gene promoters.
- PC4 stabilizes SMYD3 occupancy at target genes, facilitating transactivation.
Conclusions:
- SMYD3 and PC4 cooperate functionally to drive oncogenic gene expression.
- PC4 plays a critical role in potentiating SMYD3 activity by stabilizing its binding to target genes.
- These findings expand the known functions of SMYD3 and PC4 in gene regulation and cancer.
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