論文 - 詳細
| RRC ID | 66863 |
|---|---|
| 著者 | Xing M, Ooi WF, Tan J, Qamra A, Lee PH, Li Z, Xu C, Padmanabhan N, Lim JQ, Guo YA, Yao X, Amit M, Ng LM, Sheng T, Wang J, Huang KK, Anene-Nzelu CG, Ho SWT, Ray M, Ma L, Fazzi G, Lim KJ, Wijaya GC, Zhang S, Nandi T, Yan T, Chang MM, Das K, Isa ZFA, Wu J, Poon PSY, Lam YN, Lin JS, Tay ST, Lee MH, Tan ALK, Ong X, White K, Rozen SG, Beer M, Foo RSY, Grabsch HI, Skanderup AJ, Li S, Teh BT, Tan P. |
| タイトル | Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer. |
| ジャーナル | J Clin Invest |
| Abstract |
Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA-binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1. |
| 巻・号 | 130(6) |
| ページ | 3005-3020 |
| 公開日 | 2020-6-1 |
| DOI | 10.1172/JCI126726 |
| PII | 126726 |
| PMID | 32364535 |
| PMC | PMC7260007 |
| MeSH | Cell Line, Tumor Epigenomics* Gene Expression Regulation, Enzymologic* Gene Expression Regulation, Neoplastic* Humans Mutation Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Response Elements Stomach Neoplasms / genetics Stomach Neoplasms / metabolism* Telomerase / biosynthesis* Telomerase / genetics Trans-Activators / genetics Trans-Activators / metabolism* |
| IF | 11.864 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | LMSU(RCB1062) GSS(RCB2277) HGC-27(RCB0500) |