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Putting SMYD3 on the MAP

Stanford University and GlaxoSmithKline plc researchers have uncovered the mechanism of action of SMYD3, a histone lysine methyltransferase overexpressed in many lung and pancreatic tumors.1 The surprise was that SMYD3 acts in the cytoplasm to regulate the MAPK pathway and not in the nucleus as previously thought. The discovery implies that inhibiting the enzyme can counter activating mutations in MAPK pathway components such as K-Ras.

SMYD3 (SET and MYND domain containing 3) is a member of a family of histone lysine methyltransferases that typically are epigenetic regulators of chromatin structure in the nucleus.2

Now, a team co-led by Julien Sage and Or Gozani has found a previously unknown function for SMYD3 in cancer. Rather than working in the nucleus as expected, SMYD3 promotes cancer growth by regulating a branch of the cytoplasmic MAPK signaling pathway.

Sage is an associate professor of pediatrics and genetics at the Stanford University School of Medicine. Gozani is an associate professor of biology at Stanford University.

The findings suggest that SMYD3 inhibitors could complement MAPK pathway inhibitors such as GSK's Mekinist trametinib. Mekinist is marketed to treat melanoma with activating mutations in the upstream MAPK pathway regulator BRAF. The drug is in

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