PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer.
PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer.
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PRMT1增强结直肠癌中NONO的致癌精氨酸甲基化
DOI：
10.1038/s41388-020-01617-0
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Wan XB
中科院分区：
文献类型：
--
作者：
Yin XK;Wang YL;Wang F;Feng WX;Bai SM;Zhao WW;Feng LL;Wei MB;Qin CL;Wang F;Chen ZL;Yi HJ;Huang Y;Xie PY;Kim T;Wang YN;Hou JW;Li CW;Liu Q;Fan XJ;Hung MC;Wan XB
精氨酸甲基化是蛋白精氨酸甲基转移酶（PRMTs）催化的一种重要的翻译后修饰。然而，PRMTs在结直肠癌（CRC）进展中的作用尚不清楚。本文报道了非pou结构域的八聚体结合蛋白（NONO）在结直肠癌组织中过表达，是结直肠癌患者预后不良的潜在标志。NONO沉默导致CRC细胞的增殖、迁移和侵袭减少，而过表达则有相反的效果。在异种移植模型中，来自nono缺陷型CRC细胞的肿瘤比来自野生型（WT）细胞的肿瘤小，PRMT1抑制阻止了CRC异种移植的进展。质谱分析表明NONO是PRMT1的底物。NONO的R251在体外和体内均被PRMT1不对称二甲基化。与NONO WT细胞相比，表达NONO R251K突变的CRC细胞表现出增殖、迁移和侵袭的减少，PRMT1敲除或药物抑制在KRAS WT和突变的CRC细胞中消除了与NONO不对称二甲基化相关的恶性表型。与邻近正常组织相比，临床标本中PRMT1在结直肠癌区高表达，这与局部晚期结直肠癌患者较差的总生存率相关。这些结果表明，PRMT1介导的R251位点NONO的甲基化促进了结直肠癌的生长和转移，并提示PRMT1抑制可能是一种有效的治疗策略，无论KRAS突变状态如何。
Arginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.
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DOI：
10.6004/jnccn.2018.0061
发表时间：
2018-07
期刊：
Journal of the National Comprehensive Cancer Network : JNCCN
影响因子：
--
作者：
Benson AB;Venook AP;Al-Hawary MM;Cederquist L;Chen YJ;Ciombor KK;Cohen S;Cooper HS;Deming D;Engstrom PF;Grem JL;Grothey A;Hochster HS;Hoffe S;Hunt S;Kamel A;Kirilcuk N;Krishnamurthi S;Messersmith WA;Meyerhardt J;Mulcahy MF;Murphy JD;Nurkin S;Saltz L;Sharma S;Shibata D;Skibber JM;Sofocleous CT;Stoffel EM;Stotsky-Himelfarb E;Willett CG;Wuthrick E;Gregory KM;Gurski L;Freedman-Cass DA
通讯作者：
Freedman-Cass DA
影响因子：
4.6
作者：
Ho TT;Huang J;Zhou N;Zhang Z;Koirala P;Zhou X;Wu F;Ding X;Mo YY
通讯作者：
Mo YY
影响因子：
8
作者：
Alfano, L.;Costa, C.;Pentimalli, F.
通讯作者：
Pentimalli, F.
影响因子：
4
作者：
Eram MS;Shen Y;Szewczyk M;Wu H;Senisterra G;Li F;Butler KV;Kaniskan HÜ;Speed BA;Dela Seña C;Dong A;Zeng H;Schapira M;Brown PJ;Arrowsmith CH;Barsyte-Lovejoy D;Liu J;Vedadi M;Jin J
通讯作者：
Jin J
影响因子：
14.9
作者：
Li S;Kuhne WW;Kulharya A;Hudson FZ;Ha K;Cao Z;Dynan WS
通讯作者：
Dynan WS