title: 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.forename: Mark L
authors.initials: ML
authors.lastname: McCleland
authors.forename: Kathryn
authors.initials: K
authors.lastname: Mesh
authors.forename: Edward
authors.initials: E
authors.lastname: Lorenzana
authors.forename: Vivek S
authors.initials: VS
authors.lastname: Chopra
authors.forename: Ehud
authors.initials: E
authors.lastname: Segal
authors.forename: Colin
authors.initials: C
authors.lastname: Watanabe
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.forename: Oleg
authors.initials: O
authors.lastname: Mayba
authors.forename: Murat
authors.initials: M
authors.lastname: Yaylaoglu
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C579842:CCAT1 long noncoding RNA, human; C489427:MYC protein, human