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Jun 12, 2014
 |  BC Innovations  |  Targets & Mechanisms

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 Phase II testing for solid tumors including lung cancers with K-Ras (KRAS)-activating mutations. At least 18 cancer therapeutics targeting the MAPK pathway are in development or on the market (see "Selected MAPK pathway compounds in cancer").

"SMYD3 is acting in the cytoplasm to methylate a specific target in the MAPK cascade," said Robert Copeland, EVP and CSO of Epizyme Inc.

"The demonstration of a broader role for this enzyme beyond just methylating histones speaks to the interplay between chromatin-remodeling factors and other important signaling pathways."

Under a 2011 deal, Epizyme and GSK are discovering compounds against three undisclosed epigenetic targets.

SMYD range

As part of an ongoing collaboration to characterize the function of epigenetic targets, the Stanford-GSK team started by analyzing gene expression data for 54 histone lysine methyltransferases in a panel of pancreatic cancers with high KRAS activity.

SMYD3 levels were consistently higher in the tumors than in healthy tissue, suggesting that the enzyme might contribute to cancer growth. To test this possibility, the team introduced conditionally activated Kras mutations into a Smyd3 knockout mouse. The animals were less susceptible to pancreatic...

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