Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression.
Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression.
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DOI：
10.1016/j.bbagrm.2018.10.005
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Wotton D
中科院分区：
文献类型：
--
作者：
Melhuish TA;Kowalczyk I;Manukyan A;Zhang Y;Shah A;Abounader R;Wotton D
髓鞘转录因子1 （Myt1）和Myt1l （Myt1样）是调节神经元分化的锌指转录因子。Myt1l的表达减少与胶质母细胞瘤（GBM）有关，而相关的St18最初被确定为乳腺癌的潜在肿瘤抑制因子。我们之前分析了Myt1或myt11重新表达的人GBM细胞系中基因表达的变化。这揭示了大部分重叠的基因表达变化，表明这些细胞的功能相似。在这里，我们发现Myt1或Myt1l的重新表达减少了两种不同GBM细胞系的增殖，激活了与神经元分化相关的基因表达程序，并限制了增殖性和上皮向间充质过渡基因集的表达。与此一致的是，MYT1和MYT1L的表达在侵袭性较强的胶质瘤亚型中较低。对表达Myt1或Myt1l的细胞中基因表达变化的检测表明，两者都抑制YAP1转录辅激活因子的表达，YAP1转录辅激活因子主要在Hippo信号通路中起作用。在myt表达细胞中，YAP1及其靶基因的表达降低，在人脑癌数据集中，YAP1与MYT1/MYT1L表达呈负相关。降低YAP1表达降低GBM细胞系的增殖，过表达YAP1使细胞增殖增加，克服了Myt1/Myt1l表达的抗增殖作用。最后，我们发现降低YAP1在GBM细胞系中的表达可以减缓原位肿瘤异种移植物的生长。总之，我们的数据表明Myt1和Myt1l直接抑制YAP1的表达，YAP1是一种促进增殖和GBM生长的蛋白质。
Myelin transcription factor 1 (Myt1) and Myt1l (Myt1-like) are zinc finger transcription factors that regulate neuronal differentiation. Reduced Myt1l expression has been implicated in glioblastoma (GBM), and the related St18 was originally identified as a potential tumor suppressor for breast cancer. We previously analyzed changes in gene expression in a human GBM cell line with re-expression of either Myt1 or Myt1l. This revealed largely overlapping gene expression changes, suggesting similar function in these cells. Here we show that re-expression of Myt1 or Myt1l reduces proliferation in two different GBM cell lines, activates gene expression programs associated with neuronal differentiation, and limits expression of proliferative and epithelial to mesenchymal transition gene-sets. Consistent with this, expression of both MYT1 and MYT1L is lower in more aggressive glioma sub-types. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Mytexpressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Proliferation of GBM cell lines is reduced by lowering YAP1 expression and increased with YAP1 over-expression, which overcomes the anti-proliferative effect of Myt1/Myt1l expression. Finally we show that reducing YAP1 expression in a GBM cell line slows the growth of orthotopic tumor xenografts. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth.
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影响因子：
4.7
作者：
Carlton AL;Illendula A;Gao Y;Llaneza DC;Boulton A;Shah A;Rajewski RA;Landen CN;Wotton D;Bushweller JH
通讯作者：
Bushweller JH
影响因子：
64.5
作者：
Bellefroid, EJ;Bourguignon, C;Pieler, T
通讯作者：
Pieler, T
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J
DOI：
10.1056/nejmoa1402121
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cancer Genome Atlas Research Network;Brat DJ;Verhaak RG;Aldape KD;Yung WK;Salama SR;Cooper LA;Rheinbay E;Miller CR;Vitucci M;Morozova O;Robertson AG;Noushmehr H;Laird PW;Cherniack AD;Akbani R;Huse JT;Ciriello G;Poisson LM;Barnholtz-Sloan JS;Berger MS;Brennan C;Colen RR;Colman H;Flanders AE;Giannini C;Grifford M;Iavarone A;Jain R;Joseph I;Kim J;Kasaian K;Mikkelsen T;Murray BA;O'Neill BP;Pachter L;Parsons DW;Sougnez C;Sulman EP;Vandenberg SR;Van Meir EG;von Deimling A;Zhang H;Crain D;Lau K;Mallery D;Morris S;Paulauskis J;Penny R;Shelton T;Sherman M;Yena P;Black A;Bowen J;Dicostanzo K;Gastier-Foster J;Leraas KM;Lichtenberg TM;Pierson CR;Ramirez NC;Taylor C;Weaver S;Wise L;Zmuda E;Davidsen T;Demchok JA;Eley G;Ferguson ML;Hutter CM;Mills Shaw KR;Ozenberger BA;Sheth M;Sofia HJ;Tarnuzzer R;Wang Z;Yang L;Zenklusen JC;Ayala B;Baboud J;Chudamani S;Jensen MA;Liu J;Pihl T;Raman R;Wan Y;Wu Y;Ally A;Auman JT;Balasundaram M;Balu S;Baylin SB;Beroukhim R;Bootwalla MS;Bowlby R;Bristow CA;Brooks D;Butterfield Y;Carlsen R;Carter S;Chin L;Chu A;Chuah E;Cibulskis K;Clarke A;Coetzee SG;Dhalla N;Fennell T;Fisher S;Gabriel S;Getz G;Gibbs R;Guin R;Hadjipanayis A;Hayes DN;Hinoue T;Hoadley K;Holt RA;Hoyle AP;Jefferys SR;Jones S;Jones CD;Kucherlapati R;Lai PH;Lander E;Lee S;Lichtenstein L;Ma Y;Maglinte DT;Mahadeshwar HS;Marra MA;Mayo M;Meng S;Meyerson ML;Mieczkowski PA;Moore RA;Mose LE;Mungall AJ;Pantazi A;Parfenov M;Park PJ;Parker JS;Perou CM;Protopopov A;Ren X;Roach J;Sabedot TS;Schein J;Schumacher SE;Seidman JG;Seth S;Shen H;Simons JV;Sipahimalani P;Soloway MG;Song X;Sun H;Tabak B;Tam A;Tan D;Tang J;Thiessen N;Triche T Jr;Van Den Berg DJ;Veluvolu U;Waring S;Weisenberger DJ;Wilkerson MD;Wong T;Wu J;Xi L;Xu AW;Yang L;Zack TI;Zhang J;Aksoy BA;Arachchi H;Benz C;Bernard B;Carlin D;Cho J;DiCara D;Frazer S;Fuller GN;Gao J;Gehlenborg N;Haussler D;Heiman DI;Iype L;Jacobsen A;Ju Z;Katzman S;Kim H;Knijnenburg T;Kreisberg RB;Lawrence MS;Lee W;Leinonen K;Lin P;Ling S;Liu W;Liu Y;Liu Y;Lu Y;Mills G;Ng S;Noble MS;Paull E;Rao A;Reynolds S;Saksena G;Sanborn Z;Sander C;Schultz N;Senbabaoglu Y;Shen R;Shmulevich I;Sinha R;Stuart J;Sumer SO;Sun Y;Tasman N;Taylor BS;Voet D;Weinhold N;Weinstein JN;Yang D;Yoshihara K;Zheng S;Zhang W;Zou L;Abel T;Sadeghi S;Cohen ML;Eschbacher J;Hattab EM;Raghunathan A;Schniederjan MJ;Aziz D;Barnett G;Barrett W;Bigner DD;Boice L;Brewer C;Calatozzolo C;Campos B;Carlotti CG Jr;Chan TA;Cuppini L;Curley E;Cuzzubbo S;Devine K;DiMeco F;Duell R;Elder JB;Fehrenbach A;Finocchiaro G;Friedman W;Fulop J;Gardner J;Hermes B;Herold-Mende C;Jungk C;Kendler A;Lehman NL;Lipp E;Liu O;Mandt R;McGraw M;Mclendon R;McPherson C;Neder L;Nguyen P;Noss A;Nunziata R;Ostrom QT;Palmer C;Perin A;Pollo B;Potapov A;Potapova O;Rathmell WK;Rotin D;Scarpace L;Schilero C;Senecal K;Shimmel K;Shurkhay V;Sifri S;Singh R;Sloan AE;Smolenski K;Staugaitis SM;Steele R;Thorne L;Tirapelli DP;Unterberg A;Vallurupalli M;Wang Y;Warnick R;Williams F;Wolinsky Y;Bell S;Rosenberg M;Stewart C;Huang F;Grimsby JL;Radenbaugh AJ;Zhang J
通讯作者：
Zhang J
影响因子：
5.3
作者：
Bjerke, Glen A.;Hyman-Walsh, Cathy;Wotton, David
通讯作者：
Wotton, David