CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer
Mark L. McCleland, … , Florian Gnad, Ron Firestein
Mark L. McCleland, … , Florian Gnad, Ron Firestein
Published January 11, 2016
Citation Information: J Clin Invest. 2016;126(2):639-652. https://doi.org/10.1172/JCI83265.
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Research Article Oncology

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.

Authors

Mark L. McCleland, Kathryn Mesh, Edward Lorenzana, Vivek S. Chopra, Ehud Segal, Colin Watanabe, Benjamin Haley, Oleg Mayba, Murat Yaylaoglu, Florian Gnad, Ron Firestein

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Figure 6

lncRNAs are associated with tissue-specific cMYC superenhancers and predict sensitivity to BET inhibition.

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lncRNAs are associated with tissue-specific cMYC superenhancers and pred...
(A) Genome browser tracks showing H3K27ac signal for colon cancer (HCT 116, blue), prostate cancer (VCaP, red), and leukemia (Jurkat, black) overlapping lncRNA-encoding genes near the cMYC locus. The y axis represents reads per million. (B) Box and whisker plot of CCAT1, PCAT1, and LOC728724 RNA expression in a panel of cancers. Data were analyzed using RNA-seq data sets from TCGA. (C) Correlation analysis of CCAT1 expression and cMYC downregulation following JQ1 treatment. Cells were treated for 24 hours with DMSO or 1 μM JQ1, and cMYC expression was quantified by qPCR. Each dot represents a single cell line. (D) Correlation analysis of CCAT1 expression and cell line sensitivity to JQ1. Relative EC50 values were calculated on the basis of 3 days of JQ1 treatment. Cell lines with an RPKM of 0.1 or less were defined as CCAT1lo, and cell lines with an RPKM of 1 or more were defined as CCAT1hi. Each dot represents a single cell line. Data represent the mean ± SEM. (E) Correlation analysis of cMYC expression and cell line sensitivity to JQ1. cMYClo and cMYChi lines were defined as being above or below the median cMYC RPKM values within each cancer type, respectively. Each dot represents a single cell line. Data represent the mean ± SEM. Statistical comparisons were made using a 2-tailed Student’s t test.