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CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer.

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.

SUBMITTER: McCleland ML

PROVIDER: S-EPMC4731162 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer.

McCleland Mark L ML Mesh Kathryn K Lorenzana Edward E Chopra Vivek S VS Segal Ehud E Watanabe Colin C Haley Benjamin B Mayba Oleg O Yaylaoglu Murat M Gnad Florian F Firestein Ron R

The Journal of clinical investigation 20160111 2

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 ...[more]

PMID: 26752646

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Project description:BackgroundColorectal cancer (CRC) is one of the most fatal malignancies worldwide, and this is in part due to high rates of tumor recurrence in these patients. Currently, TNM staging remains the gold standard for predicting prognosis and recurrence in CRC patients; however, this approach is inadequate for identifying high-risk patients with the highest likelihood of disease recurrence. Recent evidence has revealed that enhancer RNAs (eRNAs) represent a higher level of cellular regulation, and their expression is frequently dysregulated in several cancers, including CRC. However, the clinical significance of eRNAs as recurrence predictor biomarkers in CRC remains unexplored, which is the primary aim of this study.ResultsWe performed a systematic analysis of eRNA expression profiles in colon cancer (CC) and rectal cancer (RC) patients from the TCGA dataset. By using rigorous biomarker discovery approaches by splitting the entire dataset into a training and testing cohort, we identified a 22-eRNA panel in CC and a 19-eRNA panel in RC for predicting tumor recurrence. The Kaplan-Meier analysis showed that biomarker panels robustly stratified low and high-risk CC (p = 7.29 × 10-5) and RC (p = 6.81 × 10-3) patients with recurrence. Multivariate and LASSO Cox regression models indicated that both biomarker panels were independent predictors of recurrence and significantly superior to TNM staging in CC (HR = 11.89, p = 9.54 × 10-4) and RC (HR = 3.91, p = 3.52 × 10-2). Notably, the ROC curves demonstrated that both panels exhibited excellent recurrence prediction accuracy in CC (AUC = 0.833; 95% CI: 0.74-0.93) and RC (AUC = 0.834; 95% CI: 0.72-0.92) patients. Subsequently, a combination signature that included the eRNA panels and TNM staging achieved an even greater predictive accuracy in patients with CC (AUC = 0.85).ConclusionsHerein, we report a novel eRNA signature for predicting recurrence in patients with CRC. Further experimental validation in independent clinical cohorts, these biomarkers can potentially improve current risk stratification approaches for guiding precision oncology treatments in patients suffering from this lethal malignancy.

Dataset Information

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer.

Publications

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer.

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