Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

被引：159

作者：

Diaz-Lagares, Angel ^{[1
]}

Crujeiras, Ana B. ^{[1
,2
,3
]}

Lopez-Serra, Paula ^{[1
]}

Soler, Marta ^{[1
]}

Setien, Fernando ^{[1
]}

Goyal, Ashish ^{[4
,5
]}

Sandoval, Juan ^{[1
]}

Hashimoto, Yutaka ^{[1
]}

Martinez-Cardus, Anna ^{[1
]}

Gomez, Antonio ^{[1
]}

Heyn, Holger ^{[1
]}

Moutinho, Catia ^{[1
]}

Espada, Jesus ^{[6
,7
]}

Vidal, August ^{[8
]}

Paules, Maria ^{[8
]}

Galan, Maica ^{[9
]}

Sala, Nuria ^{[10
]}

Akiyama, Yoshimitsu ^{[11
]}

Martinez-Iniesta, Maria ^{[12
]}

Farre, Lourdes ^{[12
,13
,14
]}

Villanueva, Alberto ^{[12
]}

Gross, Matthias ^{[4
,5
]}

Diederichs, Sven ^{[4
,5
,15
,16
,17
]}

Guil, Sonia ^{[1
]}

Esteller, Manel ^{[1
,18
,19
]}

机构：

[1] Bellvitge Biomed Res Inst IDIBELL, PEBC, Barcelona 08908, Catalonia, Spain

[2] Inst Salud Carlos III, Ctr Invest Biomed Red CIBER Fisiopatol Obesidad &, Madrid 28029, Spain

[3] Complejo Hosp Univ Santiago, Endocrine Div, Santiago De Compostela 15706, Spain

[4] German Canc Res Ctr, Div RNA Biol & Canc B150, D-69120 Heidelberg, Germany

[5] Univ Heidelberg Hosp, Inst Pathol, D-69120 Heidelberg, Germany

[6] Ramon Y Cajal Univ Hosp, Ramon Y Cajal Inst Biomed Res IRYCIS, Expt Dermatol & Skin Biol Grp, Madrid 28034, Spain

[7] Bernardo OHiggins Univ, Bionanotechnol Lab, Santiago 8370854, Chile

[8] Hosp Univ Bellvitge, IDIBELL, Dept Pathol, Barcelona 08907, Catalonia, Spain

[9] IDIBELL, Catalan Inst Oncol, Dept Med Oncol, Barcelona 08908, Catalonia, Spain

[10] IDIBELL, ICO, Canc Epidemiol Res Program, Unit Nutr & Canc, Barcelona 08908, Catalonia, Spain

[11] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Mol Oncol, Tokyo 1138510, Japan

[12] IDIBELL, ICO, Program Canc Therapeut Resistance ProCURE, Barcelona 08908, Catalonia, Spain

[13] Oswaldo Cruz Fdn CPQGM FIOCRUZ, Goncalo Moniz Res Ctr, Lab Expt Pathol LAPEX, BR-40296710 Salvador, BA, Brazil

[14] Natl Inst Sci & Technol Trop Dis INCT DT, BR-40296710 Salvador, BA, Brazil

[15] Univ Freiburg, Med Ctr, Dept Thorac Surg, Div Canc Res, D-79106 Freiburg, Germany

[16] Univ Freiburg, Fac Med, D-79106 Freiburg, Germany

[17] German Canc Consortium DKTK, D-79106 Freiburg, Germany

[18] Univ Barcelona, Escola Med, Dept Ciencies Fisiol 2, Barcelona 08907, Catalonia, Spain

[19] ICREA, Barcelona 08010, Catalonia, Spain

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 47期

基金：

欧洲研究理事会;

关键词：

DNA methylation; long noncoding RNA; epigenetics; cancer; TRANSLATIONAL ACTIVATION; CHROMATIN STATE; YB-1; PROMOTES; GENE; TRANSCRIPTION; DNA; PROGRESSION; P53; EXPRESSION; BOX;

D O I：

10.1073/pnas.1608585113

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell.

引用

页码：E7535 / E7544

页数：10

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