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Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer.

SUBMITTER: Reynoird N

PROVIDER: S-EPMC4826394 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer.

Reynoird Nicolas N Mazur Pawel K PK Stellfeld Timo T Flores Natasha M NM Lofgren Shane M SM Carlson Scott M SM Brambilla Elisabeth E Hainaut Pierre P Kaznowska Ewa B EB Arrowsmith Cheryl H CH Khatri Purvesh P Stresemann Carlo C Gozani Or O Sage Julien J

Genes & development 20160317 7

Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Final ...[more]

PMID: 26988419

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Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression.

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The Lysine Methyltransferase SMYD2 Is Required for Definite Hematopoietic Stem Cell Production in the Mouse Embryo.

Project description:The five-membered SET and MYND domain-containing lysine methyltransferase (SMYD) family plays pivotal roles in development and differentiation. Initially characterized within the cardiovascular system, one such member, SMYD2, has been implicated in transcriptional and apoptotic regulation of hematopoiesis. Deletion of Smyd2 in adult mouse Hemaopoietic Stem Cells (HSC) using an interferon-inducible mx1-Cre-mediated conditional knockout (CKO) led to HSC reduction via both apoptosis and transcriptional deficiencies. Since HSC are specified from hemogenic endothelial (HE) cells in the dorsal aorta (DA), we sought to determine whether the flaw in HSC originated embryologically from this site. Toward this end, we performed deletion with vav-Cre mice, which is active in all hematopoietic and endothelial tissues from E10.5 embryonic life onward. Unexpectedly, we observed no defects in the embryo, other than apoptotic loss of definite HSC, whereas adult hematopoietic populations downstream were unaffected. These results further establish the importance of SMYD2 in antiapoptotic gene control of gene expression from the embryo to the adult.

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