CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer.
J Clin Invest
; 126(2): 639-52, 2016 Feb.
Article
em En
| MEDLINE
| ID: mdl-26752646
ABSTRACT
Colon tumors arise in a stepwise fashion from either discrete genetic perturbations or epigenetic dysregulation. To uncover the key epigenetic regulators that drive colon cancer growth, we used a CRISPR loss-of-function screen and identified a number of essential genes, including the bromodomain and extraterminal (BET) protein BRD4. We found that BRD4 is critical for colon cancer proliferation, and its knockdown led to differentiation effects in vivo. JQ1, a BET inhibitor, preferentially reduced growth in a subset of epigenetically dysregulated colon cancers characterized by the CpG island methylator phenotype (CIMP). Integrated transcriptomic and genomic analyses defined a distinct superenhancer in CIMP+ colon cancers that regulates cMYC transcription. We found that the long noncoding RNA colon cancer-associated transcript 1 (CCAT1) is transcribed from this superenhancer and is exquisitely sensitive to BET inhibition. Concordantly, cMYC transcription and cell growth were tightly correlated with the presence of CCAT1 RNA in a variety of tumor types. Taken together, we propose that CCAT1 is a clinically tractable biomarker for identifying patients who are likely to benefit from BET inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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RNA Neoplásico
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Proteínas Nucleares
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Biomarcadores Tumorais
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Proliferação de Células
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RNA Longo não Codificante
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2016
Tipo de documento:
Article