Abstract A23: SMYD3 links methylation of MAP3K2 to Ras-driven tumors

Abstract

Abstract The Ras family of oncogenes is activated in a large fraction of human cancers. Treatment of Ras-driven tumors with inhibitors of protein kinases in the Ras signaling network, such as Raf or MEK is a promising therapeutic strategy. However, toxicity issues and the emergence of tumor cells that are resistant to these drugs underscore the need for a better understanding of the Ras pathway and for the development of novel therapeutic options to improve the survival of cancer patients. Deregulation in lysine methylation signaling has emerged as a common etiologic factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumors. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP Kinase signaling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LAC), we found that abrogating SMYD3 catalytic activity inhibits tumor development in response to oncogenic Ras. We employed protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signaling module. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP Kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signaling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signaling. Citation Format: Pawel K. Mazur, Nicolas Reynoird, Purvesh Khatri, Atul J. Butte, Alex Wilkinson, Benjamin Garcia, Shichong Liu, Michiel Vermeulen, Pascal W.T.C. Jansen, Peter J. Tummino, Ryan G. Kruger, Glenn S. Van Aller, Olena Barbash, Michael Huddleston, Or Gozani, Julien Sage. SMYD3 links methylation of MAP3K2 to Ras-driven tumors. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A23.