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

被引：71

作者：

Reynoird, Nicolas ^{[1
,2
]}

Mazur, Pawel K. ^{[3
,4
]}

Stellfeld, Timo ^{[5
]}

Flores, Natasha M. ^{[3
,4
]}

Lofgren, Shane M. ^{[6
,7
]}

Carlson, Scott M. ^{[1
]}

Brambilla, Elisabeth ^{[2
]}

Hainaut, Pierre ^{[2
]}

Kaznowska, Ewa B. ^{[8
]}

Arrowsmith, Cheryl H. ^{[9
,10
]}

Khatri, Purvesh ^{[6
,7
]}

Stresemann, Carlo ^{[5
]}

Gozani, Or ^{[1
]}

Sage, Julien ^{[3
,4
]}

机构：

[1] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[2] Univ Grenoble Alpes, Inst Natl Sante & Rech Med, Ctr Natl Rech Sci, Inst Albert Bonniot,U1209,UMR5309, F-38700 Grenoble, France

[3] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[5] Bayer Pharma AG, Global Drug Discovery, D-13353 Berlin, Germany

[6] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[7] Stanford Univ, Inst Immun Transplantat & Infect, Sch Med, Stanford, CA 94305 USA

[8] Univ Rzeszow, Fac Med, Ctr Innovat Res Med & Nat Sci, PL-35959 Rzeszow, Poland

[9] Univ Toronto, Princess Margaret Canc Ctr, Struct Genom Consortium, Toronto, ON M5G 2M9, Canada

[10] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

来源：

GENES & DEVELOPMENT | 2016年 / 30卷 / 07期

基金：

加拿大创新基金会; 巴西圣保罗研究基金会; 美国国家卫生研究院; 英国惠康基金;

关键词：

Ras; SMYD2; MAPKAPK3; pancreatic cancer; lung adenocarcinoma; lysine methylation; ACTIVATED PROTEIN-KINASE; HISTONE METHYLTRANSFERASE; DUCTAL ADENOCARCINOMA; MAPKAP KINASES; MOUSE MODEL; INTRAEPITHELIAL NEOPLASIA; GEMCITABINE-RESISTANCE; CELL PROLIFERATION; ALPHA PRODUCTION; BREAST-CANCER;

D O I：

10.1101/gad.275529.115

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：772 / 785

页数：14

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