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

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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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.

Original languageEnglish
Pages (from-to)639-652
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016
Externally publishedYes

Cite this

McCleland, Mark L. ; Mesh, Kathryn ; Lorenzana, Edward ; Chopra, Vivek S. ; Segal, Ehud ; Watanabe, Colin ; Haley, Benjamin ; Mayba, Oleg ; Yaylaoglu, Murat ; Gnad, Florian ; Firestein, Ron. / CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 2. pp. 639-652.
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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.",
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McCleland, ML, Mesh, K, Lorenzana, E, Chopra, VS, Segal, E, Watanabe, C, Haley, B, Mayba, O, Yaylaoglu, M, Gnad, F & Firestein, R 2016, 'CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer', Journal of Clinical Investigation, vol. 126, no. 2, pp. 639-652. https://doi.org/10.1172/JCI83265

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. / McCleland, Mark L.; Mesh, Kathryn; Lorenzana, Edward; Chopra, Vivek S.; Segal, Ehud; Watanabe, Colin; Haley, Benjamin; Mayba, Oleg; Yaylaoglu, Murat; Gnad, Florian; Firestein, Ron.

In: Journal of Clinical Investigation, Vol. 126, No. 2, 01.02.2016, p. 639-652.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Gnad, Florian

AU - Firestein, Ron

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McCleland ML, Mesh K, Lorenzana E, Chopra VS, Segal E, Watanabe C et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. Journal of Clinical Investigation. 2016 Feb 1;126(2):639-652. https://doi.org/10.1172/JCI83265