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 7

Patients with colon tumors expressing high CCAT1 levels have a poor clinical outcome.

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Patients with colon tumors expressing high CCAT1 levels have a poor clin...
(A) Representative ISH photomicrographs show CCAT1 expression in colon tumors. The ISH scoring system is indicated. Scale bar: 100 μm. (B) ISH score breakdown for a panel of normal colon and colon tumors. Each patient sample was scored from triplicate representative tumor cores, and the average CCAT1 ISH score was recorded as low (score of 0–1), moderate (score of 1–2), or high (score of 2–3). (C) Kaplan-Meier survival data for patients with colon cancer, separated by CCAT1 ISH score (CCAT1– patients are defined by an ISH score <1, and CCAT1+ patients are defined by an ISH score >1). Separate curves are shown for overall survival and colon cancer–specific survival. PH, proportional hazards. (D) Model highlighting the utility of lncRNAs in identifying lineage-dependent superenhancers in different cancer types. The model predicts that cMYC-dependent tumors driven by BET and associated superenhancers will be more responsive to BET inhibitors. CNG, copy number gain.