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Updated: May 29, 2025

In vitro Organoid Culture of Primary Mouse Colon Tumors
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Published on: May 17, 2013

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HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis

Li Z Luo1, Jung-Hyun Kim1,2, Iliana Herrera1

  • 1Division of Hematology, Department of Medicine, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

The Journal of Clinical Investigation
|February 3, 2025
PubMed

Insights

HMGA1 acts as an epigenetic regulator, amplifying Wnt signaling to drive colon cancer by promoting stem cell states. Reducing HMGA1 restrains tumor growth, highlighting its therapeutic potential.

Area of Science:

  • Molecular biology
  • Epigenetics
  • Cancer research

Background:

  • Tumorigenesis involves altered chromatin accessibility and gene expression.
  • HMGA1 is implicated in various cancers but its role in colon tumorigenesis is emerging.
  • Wnt signaling is crucial in colon cancer development.

Purpose of the Study:

  • To investigate the role of HMGA1 in colon tumorigenesis.
  • To elucidate the epigenetic mechanisms by which HMGA1 influences Wnt signaling and cell states.
  • To assess HMGA1 as a potential therapeutic target in colorectal cancer.

Main Methods:

  • Analysis of chromatin accessibility and gene expression in colon cancer models.
  • Investigating the interaction of HMGA1 with Wnt signaling pathways.
  • Assessing the impact of HMGA1 modulation on tumor growth and cell differentiation.
  • Examining HMGA1 and ASCL2 expression in human colorectal cancer samples.

Main Results:

  • HMGA1 amplifies Wnt signaling by upregulating the stem cell regulator Ascl2, promoting stem and Paneth-like cell states.
  • Loss of one Hmga1 allele restrains tumorigenesis driven by Apc inactivation and inflammatory microbiota.
  • HMGA1 directly induces ASCL2 in human colon cancer cells by recruiting activating histone marks.
  • HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer.

Conclusions:

  • HMGA1 acts as an epigenetic gatekeeper of Wnt signaling and cell state during APC-inactivated colon tumorigenesis.
  • HMGA1 drives colon cancer progression by maintaining stem cell properties and promoting aberrant proliferation.
  • HMGA1 represents a promising therapeutic target for colorectal cancer treatment.
Keywords:
Colorectal cancerEpigeneticsOncologyTranscription

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