Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression

被引：172

作者：

Jiang, Yuan ^{[1
]}

Jiang, Yan-Yi ^{[1
]}

Xie, Jian-Jun ^{[2
]}

Mayakonda, Anand ^{[1
]}

Hazawa, Masaharu ^{[3
]}

Chen, Li ^{[4
]}

Xiao, Jin-Fen ^{[1
]}

Li, Chun-Quan ^{[5
]}

Huang, Mo-Li ^{[1
]}

Ding, Ling-Wen ^{[1
]}

Sun, Qiao-Yang ^{[1
]}

Xu, Liang ^{[1
]}

Kanojia, Deepika ^{[1
]}

Jeitany, Maya ^{[1
]}

Deng, Jian-Wen ^{[2
]}

Liao, Lian-Di ^{[6
]}

Soukiasian, Harmik J. ^{[7
]}

Berman, Benjamin P. ^{[8
]}

Hao, Jia-Jie ^{[9
,10
]}

Xu, Li-Yan ^{[6
]}

Li, En-Min ^{[2
]}

Wang, Ming-Rong ^{[9
,10
]}

Bi, Xin-Gang ^{[10
,11
]}

Lin, De-Chen ^{[4
]}

Koeffler, H. Phillip ^{[1
,4
,12
]}

机构：

[1] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117599, Singapore

[2] Shantou Univ, Med Coll, Dept Biochem & Mol Biol, Shantou 515041, Peoples R China

[3] Kanazawa Univ, Inst Frontier Sci Initiat, Innovat Integrated Biores Core, Cell Bion Res Unit, Kanazawa, Ishikawa 9201192, Japan

[4] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA

[5] Harbin Med Univ, Sch Med Informat, Daqing Campus, Daqing 163319, Peoples R China

[6] Shantou Univ, Med Coll, Inst Oncol Pathol, Shantou 515041, Peoples R China

[7] Cedars Sinai Med Ctr, Dept Surg, Los Angeles, CA 90048 USA

[8] Cedars Sinai Med Ctr, Ctr Bioinformat & Funct Genom, Los Angeles, CA 90048 USA

[9] Chinese Acad Med Sci, Canc Hosp, Natl Clin Res Ctr, State Key Lab Mol Oncol,Natl Canc Ctr, Beijing 100021, Peoples R China

[10] Peking Union Med Coll, Beijing 100021, Peoples R China

[11] Chinese Acad Med Sci, Canc Hosp, Natl Clin Res Ctr Canc, Dept Urol,Natl Canc Ctr, Beijing 100021, Peoples R China

[12] Natl Univ Singapore Hosp, Natl Univ Canc Inst, Singapore 119074, Singapore

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

新加坡国家研究基金会; 中国国家自然科学基金;

关键词：

LONG NONCODING RNAS; COMPREHENSIVE GENOMIC CHARACTERIZATION; CELL-PROLIFERATION; REGENERATIVE PROLIFERATION; C-MYC; CARCINOMA; P63; TRANSCRIPTION; EXPRESSION; ACTIVATION;

D O I：

10.1038/s41467-018-06081-9

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：

07 ; 0710 ; 09 ;

摘要：

Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage specifically regulate long non-coding RNA (IncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.

引用

页数：13

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