title: A dynamic exchange of TCF3 and TCF4 transcription factors controls MYC expression in colorectal cancer cells.
abstract: Deregulated Wnt/β-catenin signaling promotes colorectal cancer (CRC) by activating expression of the c-MYC proto-oncogene (MYC). In the nucleus, the β-catenin transcriptional co-activator binds T-cell factor (TCF) transcription factors, and together TCF/β-catenin complexes activate MYC expression through Wnt responsive DNA regulatory elements (WREs). The MYC 3' WRE maps 1.4-kb downstream from the MYC transcription stop site and binds TCF4/β-catenin transcription complexes to activate MYC. However, the underlying mechanisms for how this element operates are not fully understood. Here, we report that the TCF family member, TCF3, plays an important role in regulating MYC expression in CRCs. We demonstrate that TCF3 binds the MYC 3' WRE to repress MYC. When TCF3 is depleted using shRNAs, the MYC 3' WRE is more available to bind TCF4/β-catenin complexes. Stimulating downstream Wnt/β-catenin signaling by inhibiting GSK3β causes an exchange of TCF3 with TCF4/β-catenin complexes to activate MYC. Finally, this transcription factor switch at the MYC 3' WRE controls MYC expression as quiescent cells re-enter the cell cycle and progress to S phase. These results indicate that a dynamic interplay of TCF transcription factors governs MYC gene expression in CRCs.
authors: a Department of Biochemistry and Molecular Biology ; The Pennsylvania State University College of Medicine ; Hershey , PA USA.
authors: Meera
authors: M
authors: Shah
authors: Sherri A
authors: SA
authors: Rennoll
authors: Wesley M
authors: WM
authors: Raup-Konsavage
authors: Gregory S
authors: GS
authors: Yochum
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D044967:Serum; D015398:Signal Transduction / Q000187:drug effects; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D008094:Lithium; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C000715470:MAS1 protein, human; C407909:TCF3 protein, human; C532096:TCF4 protein, human
keywords: APC, adenomatous polyposis coli; CRC, colorectal cancer; ChIP, chromatin immunoprecipitation; GSK3β, glycogen synthase kinase 3 β; HDAC, histone deacetylase; Lef, Lymphoid enhancer-binding factor; LiCl, lithium chloride; MYC; MYC, myelocytomatosis; RT, reverse transcription; TCF, T-cell factor; TCF3; TCF4; TLE, Transducin-like enhancer of split; WRE; WRE, Wnt responsive DNA element; colorectal cancer; qPCR, quantitative PCR; transcription; β-catenin