title: CRNDE, a long non-coding RNA responsive to insulin/IGF signaling, regulates genes involved in central metabolism.
abstract: Colorectal neoplasia differentially expressed (CRNDE) is a novel gene that is activated early in colorectal cancer but whose regulation and functions are unknown. CRNDE transcripts are recognized as long non-coding RNAs (lncRNAs), which potentially interact with chromatin-modifying complexes to regulate gene expression via epigenetic changes. Complex alternative splicing results in numerous transcripts from this gene, and we have identified novel transcripts containing a highly-conserved sequence within intron 4 ("gVC-In4"). In colorectal cancer cells, we demonstrate that treatment with insulin and insulin-like growth factors (IGF) repressed CRNDE nuclear transcripts, including those encompassing gVC-In4. These repressive effects were negated by use of inhibitors against either the PI3K/Akt/mTOR pathway or Raf/MAPK pathway, suggesting CRNDE is a downstream target of both signaling cascades. Expression array analyses revealed that siRNA-mediated knockdown of gVC-In4 transcripts affected the expression of many genes, which showed correlation with insulin/IGF signaling pathway components and responses, including glucose and lipid metabolism. Some of the genes are identical to those affected by insulin treatment in the same cell line. The results suggest that CRNDE expression promotes the metabolic changes by which cancer cells switch to aerobic glycolysis (Warburg effect). This is the first report of a lncRNA regulated by insulin/IGFs, and our findings indicate a role for CRNDE nuclear transcripts in regulating cellular metabolism which may correlate with their upregulation in colorectal cancer.
authors.affiliation: CSIRO Animal, Food and Health Sciences, Preventative Health Flagship, Commonwealth Scientific and Industrial Research Organization, Sydney, NSW 2113 Australia. Electronic address: blake.ellis@csiro.au.
authors.forename: Blake C
authors.initials: BC
authors.lastname: Ellis
authors.affiliation: CSIRO Animal, Food and Health Sciences, Preventative Health Flagship, Commonwealth Scientific and Industrial Research Organization, Sydney, NSW 2113 Australia. Electronic address: lloyd.graham@csiro.au.
authors.forename: Lloyd D
authors.initials: LD
authors.lastname: Graham
authors.affiliation: CSIRO Animal, Food and Health Sciences, Preventative Health Flagship, Commonwealth Scientific and Industrial Research Organization, Sydney, NSW 2113 Australia. Electronic address: peter.molloy@csiro.au.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Molloy
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism* / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D008660:Metabolism / Q000187:drug effects / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D048490:raf Kinases / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051275:Glucose Transporter Type 4; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D007773:Lactates; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; C586983:CRNDE RNA, human; C116385:MLXIPL protein, human; C495692:SLC2A4 protein, human; C546842:MTOR protein, human
keywords: CRC; CRNDE; Colorectal cancer; Colorectal neoplasia differentially expressed; Genomic vertebrate conserved in intron 4; IGF1; IGF1R; IGF2; INSR; IPA; Ingenuity Pathway Analysis; Insulin; Insulin receptor; Insulin-like growth factor 1; Insulin-like growth factor 1 receptor; Insulin-like growth factor 2; Long non-coding RNA; MAPK; Mammalian target of rapamycin; Mitogen activated protein kinase; PI3K; Phosphatidylinositide 3-kinase; TCA; Tricarboxylic acid; Warburg effect; gVC-In4; lncRNA; mTOR