Abstract
SMYD3-mediated MAP3K2 methylation activates RAS signaling and drives carcinogenesis in vivo.
Major finding: SMYD3-mediated MAP3K2 methylation activates RAS signaling and drives carcinogenesis in vivo.
Mechanism: Methylation of MAP3K2 by SMYD3 disrupts binding to PP2A and activates MEK1/2 signaling.
Impact: RAS-driven cancers may be sensitive to SMYD3 inhibition alone or together with MAPK pathway inhibition.
Lysine methyltransferase (KMT) expression is frequently deregulated in human cancers, but the contributions of KMTs to oncogenic signaling pathways are not well understood. In an effort to determine whether deregulated KMT activity contributes to RAS-driven cancers, Mazur and colleagues evaluated KMT expression in pancreatic ductal adenocarcinoma, which is usually initiated by oncogenic RAS signaling, and observed increased expression of the KMT gene SMYD3. Pancreatic cancer mouse models harboring mutant Kras showed that cytoplasmic SMYD3 levels increased during KRAS-driven transformation, and Smyd3 deletion suppressed KRAS-induced pancreatic intraepithelial neoplasia and lung tumor progression and enhanced survival in association with reduced phosphorylation of ERK1/2 (pERK1/2). SMYD3 KMT activity was required for RAS-driven tumorigenesis and pERK1/2 signaling in Kras-mutant;Smyd3-deficient mice. In vitro screening of over 9,000 potential SMYD3 substrates identified MAP3K2 as a potential SMYD3 target, and biochemical experiments confirmed the specific methylation of MAP3K2 at lysine 260 by SMYD3 in vitro and in vivo. SMYD3 and MAP3K2 were both required for full activation of downstream MAP3K2 targets, and silencing of SMYD3 or MAP3K2 similarly inhibited activation of MEK1/2, suggesting that SMYD3 methylation of MAP3K2 may affect RAS signaling by directly regulating MEK1/2 function. Mechanistically, MAP3K2 methylation on lysine 260 by SMYD3 prevented binding to the PP2A serine/threonine phosphatase complex, a known inhibitor of the MAP kinase pathway, thereby potentiating MEK1/2 kinase activity. Consistent with these results suggesting SMYD3 plays a role in MEK1/2 signaling, SMYD3 depletion increased the potency of the MEK1/2 inhibitor trametinib in cancer cell lines and reduced the trametinib dose needed to suppress tumorigenesis in vivo. Together, these results highlight a role for KMT activity in regulating cytoplasmic oncogenic signaling and provide a rationale for the development of SMYD3 inhibitors in cancers driven by oncogenic RAS.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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