A recent paper in Nature Cell Biology describes the identification of a gene — SMYD3 (SET- and MYND-domain-containing-3) — that encodes a histone methyltransferase, and that is overexpressed in colorectal and hepatocellular carcinoma cell lines and tissues.

In support of a role for SMYD3 in tumorigenesis, Yusuke Nakamura and colleagues found that SMYD3 overexpression induced cell growth in vitro, whereas knockdown of SMYD3 expression with small interfering RNAs suppressed the growth of several colorectal and hepatocellular carcinoma cell lines. In addition, microarray analysis highlighted the upregulation of several genes — including proto-oncogenes, cell-cycle regulatory genes and developmental genes — in cells that were overexpressing SMYD3.

Using yeast two-hybrid and immunoprecipitation analyses, the authors showed that SMYD3 binds to the heat-shock protein HSP90A and, indirectly, to RNA polymerase II. SMYD3 specifically methylates histone H3 at lysine 4 — this type of histone methylation is important for transcriptional activation. In addition, the catalytic activity of SMYD3 was induced in the presence of HSP90A, which indicates that it functions as a co-factor for histone-methyltransferase activity.

But how are these histone modifications targeted to a particular site? Nakamura and co-workers showed that SMYD3 binds directly to a specific DNA sequence. One of the target genes that is upregulated by SMYD3, the homeobox gene Nkx2.8, indeed contains such a SMYD3-binding sequence in its promoter region. And, chromatin-immunoprecipitation experiments showed that SMYD3 binds to this region in vivo.

So, SMYD3 seems to form a transcriptional complex with RNA polymerase II and targets its histone lysine-methylation activity to specific DNA sequences by binding to the promoter region of target genes like “...a transcription factor containing histone methyltransferase activity”. In addition, SMYD3 could be an ideal therapeutic target in the treatment of certain tumours.