Smyd3 Is a Transcriptional Potentiator of Multiple Cancer-Promoting Genes and Required for Liver and Colon Cancer Development

Smyd3 is a protein methyltransferase implicated in cancer development. Here we show that Smyd3 expression in mice is required for chemically induced liver and colon cancer formation. In these organs Smyd3 functions in the nucleus, stimulating the transcription of several key regulators involved in cell proliferation, epithelial-mesenchymal transition, the JAK/Stat3 oncogenic pathway, as well as the Myc and Ctnnb1 oncogenes. Smyd3 interacts with H3K4Me3-modified histone tails, which facilitates its recruitment to the core promoter regions of most active genes. Smyd3 binding density on target genes positively correlates with increased RNA polymerase-II density and transcriptional outputs. Despite its widespread distribution, the transcription-potentiating function of Smyd3 is restricted to a particular set of genes, whose expression is induced specifically during carcinogenesis. [Display omitted] •Smyd3 is required but not sufficient for liver and colon cancer development in mice•Smyd3 expression correlates with poor clinical prognosis of human HCC•Smyd3 stimulates the transcription of genes in various cancer-related pathways•Smyd3 invades active chromatin domains via association with H3K4Me3 and RNA Pol-II Sarris et al. show that Smyd3 is required for the development of induced liver and colon cancer in mice, and in human HCC the expression of SMYD3 has prognostic value. Mechanistically Smyd3 potentiates the transcription of a number of cancer-promoting genes.