HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis
Li Z. Luo, … , Cynthia L. Sears, Linda Resar
Li Z. Luo, … , Cynthia L. Sears, Linda Resar
Published February 3, 2025
Citation Information: J Clin Invest. 2025;135(3):e184442. https://doi.org/10.1172/JCI184442.
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Research Article Oncology

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

Abstract

Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 “opens” chromatin to upregulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas reexpression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.

Authors

Li Z. Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E. West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L. Reddy, Ying Feng, Eric R. Fearon, Cynthia L. Sears, Linda Resar

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Figure 4

Hmga1 haploinsufficiency disrupts colon tumorigenesis induced by ETBF in APCMin/+ mice.

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Hmga1 haploinsufficiency disrupts colon tumorigenesis induced by ETBF i...
(A) Body weights at necropsy after ETBF in ApcMin/+ mice with intact Hmga1 or heterozygous Hmga1 (*P < 0.05, **P < 0.01, ***P < 0.001; student’s t test). (B) Representative images of methylene-blue stained colons to visualize tumors in ApcMin/+/Hmga1+/+ mouse (top) compared with ApcMin/+/Hmga1+/– mouse (bottom) at 11–12 weeks after ETBF. (C) Normalized tumor numbers in ApcMin/+ models (*P < 0.05; Mann-Whitney test). (D) Kaplan-Meier plot showing survival in in ApcMin/+ mice with intact Hmga1 or heterozygous (*P < 0.05; Mantel-Cox test). (E) Representative images (H&E left; IHC right; Scale bars: 200 μm) for HMGA1 (second column), β-catenin (third column), and Ki67 (right) in distal colon of ApcMin/+ models at 11–12 weeks after ETBF. (F) Comparison of crypt depths (**P < 0.01) and IHC for nuclear HMGA1 (**P < 0.01), nuclear β-catenin (****P < 0.0001) and Ki-67(P = 0.16, unpaired student’s t test for each comparison) in ApcMin/+ models. For crypt depth (left), each shape (circle, square, triangle, hexagon) corresponds to a different mouse (n = 3–4/genotype). The solid shapes show the mean from each mouse; the open, smaller shapes represent individual measurements/crypt (range = 9–16 crypts/mouse). For the IHC comparisons, each shape (circle, square, triangle, hexagon) corresponds to a different mouse (n = 3–4/genotype), the solid shapes show the mean value from each mouse; the open, smaller shapes represent individual values/field (range=9-19 fields/mouse) at x20 magnification.