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.
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DOI：
10.1093/nar/gkv874
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发表时间：
2015-10-15
影响因子：
14.9
通讯作者：
An W
中科院分区：
文献类型：
--
作者：
Kim JM;Kim K;Schmidt T;Punj V;Tucker H;Rice JC;Ulmer TS;An W
SET和MYND结构域蛋白3（SMYD3）是一种组蛋白甲基转移酶，与细胞生长和癌症发病机制有关。越来越多的证据表明，SMYD3可以通过作为基因特异性转录调节因子影响不同的致癌过程。然而，SMYD3反式激活的机制方面以及SMYD3是否与其他转录调节剂协同作用仍不清楚。在这里，我们表明，SMYD3与人类阳性辅激活因子4（PC4）相互作用，这种相互作用增强了一组基因的表达与细胞增殖和侵袭。SMYD3在功能上与PC4合作，因为PC4缺失导致SMYD3介导的H3K4me3和靶基因表达的丧失。SMYD3和PC4的个体消耗减少了SMYD3和PC4的募集，表明SMYD3和PC4以相互依赖的方式定位于靶基因。不能与其同源元件结合并与PC4相互作用的SMYD3突变体与靶基因的人工拴系足以在SMYD3缺陷型细胞中实现活性转录状态。这些观察结果表明，PC4有助于SMYD3介导的反式激活，主要是通过稳定SMYD3在靶基因的占有。总之，这些研究定义了SMYD3和PC4在基因调控中的扩展作用，并提供了它们在刺激致癌转录中的合作功能的前所未有的文件。
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.