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TCF7L1 Regulates LGR5 Expression in Colorectal Cancer Cells

Carli M King1,2, Olivia M Marx1,2, Wei Ding2

  • 1Department of Biochemistry & Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17036, USA.

Genes
|February 25, 2023
PubMed

Insights

TCF7L1 represses the Wnt target gene LGR5 in colorectal cancer (CRC) cells by binding a novel Wnt-responsive element (WRE). This regulation impacts CRC stem cell spheroid formation, highlighting TCF7L1

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Wnt/β-catenin signaling pathway mutations drive colorectal cancer (CRC).
  • T-cell factor (TCF) transcription factors regulate Wnt-responsive genes.
  • Leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5) is a Wnt target gene crucial for CRC stem cell plasticity.

Purpose of the Study:

  • To define Wnt-responsive elements (WREs) at the LGR5 locus.
  • To investigate how TCF factors directly regulate LGR5 expression in CRC.
  • To elucidate the role of TCF7L1 in LGR5 regulation and CRC stem cell function.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to identify TCF7L1 binding sites.
  • CRISPR activation and interference (CRISPRa/i) for epigenetic modulation.
  • Spheroid formation assays to assess CRC stem cell capacity.

Main Results:

  • TCF7L1 binds a novel promoter-proximal WRE at the LGR5 locus.
  • TCF7L1 binding represses LGR5 expression.
  • The identified WRE is critical for LGR5 expression and CRC cell spheroid formation.
  • Restoring LGR5 expression rescues TCF7L1-mediated reduction in spheroid formation.

Conclusions:

  • TCF7L1 acts as a repressor of LGR5 expression in CRC cells.
  • TCF7L1 regulates CRC stem cell spheroid formation potential via LGR5.
  • The novel TCF7L1-binding WRE at the LGR5 locus is a key regulatory element.
Keywords:
LGR5T-cell factorsTCF7L1WNTWnt-responsive DNA elementscolorectal cancerspheroids

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