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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.
Insights
Researchers identified BRD4 as a key epigenetic regulator in colon cancer. Targeting BRD4 with inhibitors like JQ1 shows promise, particularly in cancers with specific epigenetic profiles, suggesting CCAT1 as a predictive biomarker.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Oncology
- Genomics and Transcriptomics
Background:
- Colon tumors develop through genetic mutations or epigenetic alterations.
- Identifying key epigenetic regulators is crucial for understanding colon cancer progression.
Purpose of the Study:
- To identify essential epigenetic regulators driving colon cancer growth using a CRISPR screen.
- To investigate the role of the BET protein BRD4 and its inhibitor JQ1 in colon cancer.
- To define the therapeutic potential of targeting BRD4 in specific colon cancer subtypes.
Main Methods:
- Conducted a CRISPR loss-of-function screen to identify essential genes in colon cancer.
- Utilized BET inhibitor JQ1 to assess its effect on colon cancer cell proliferation.
- Performed integrated transcriptomic and genomic analyses to identify regulatory elements and transcripts.
Main Results:
- Identified BRD4 as a critical regulator for colon cancer proliferation, with knockdown inducing differentiation.
- JQ1 preferentially inhibited growth in CpG island methylator phenotype (CIMP)-positive colon cancers.
- Discovered a superenhancer regulating cMYC in CIMP+ colon cancers, transcribing the long noncoding RNA CCAT1, which is sensitive to BET inhibition.
Conclusions:
- BRD4 plays a vital role in colon cancer growth and differentiation.
- CCAT1 RNA levels correlate with cMYC transcription and cell growth, indicating its significance in BET inhibitor response.
- CCAT1 serves as a potential biomarker for identifying colon cancer patients who may benefit from BET inhibitors.
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