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 5

Genomic approaches uncover CCAT1 as a direct BET transcriptional target and predictor of BET inhibitor sensitivity.

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Genomic approaches uncover CCAT1 as a direct BET transcriptional target ...
(A) Venn diagram shows the overlap of genes downregulated by JQ1 (>2-fold) and associated with a superenhancer across CIMP+ and CIMP– cell lines. Superenhancer-associated, JQ1-regulated genes common to all CIMP+ cell lines are highlighted. (B) Distribution of BRD4 ChIP-seq signal across enhancers in CIMP+ cell lines. The y axis represents input-subtracted BRD4 signal; the x axis represents enhancers ranked by BRD4 signal intensity. Superenhancers were defined as enhancers that surpassed the inflection point. The CCAT1-associated superenhancer is highlighted. (C) Genome browser tracks showing input-normalized average BRD4 ChIP-seq signal across the CCAT1 locus for CIMP+ (blue) and CIMP– (red) cell lines. The y axis represents BRD4/input coverage values averaged for CIMP+ (HT-29, COLO 205, HCT 116, HCT 15) or CIMP– (SW 480, COLO 320) cell lines. (D) Basal RNA levels of CCAT1 in colon cell lines. RNA was measured by RNA-seq. Blue bars represent CIMP+ lines; red bars represent CIMP– lines. (E) Relative CCAT1 expression in CIMP+ cells following treatment with 500 nM JQ1. Data are from RNA-seq analysis and represent the mean ± SD. (F) Relative cMYC expression in colon cancer cells following treatment with 500 nM JQ1. Data are from RNA-seq analysis and represent the mean ± SD. Blue bars represent CIMP+ lines; red bars represent CIMP– lines.