HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC

Colorectal cancer is the second leading cause of cancer death in the United States. The adenomatous polyposis coli (APC) pathway plays a critical role in colorectal tumorigenesis, but the mechanism is not fully understood. In this issue of the JCI, Luo and colleagues used genetically engineered mouse models to show that high mobility group A (HMGA1) is a critical mediator in the development of colon tumors driven by the loss of the Apc gene. HMGA1 activated the transcription of Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2), which regulated intestinal stemness and promoted colon tumorigenesis.

Colorectal cancer is the second leading cause of cancer death in the United States, with 153,000 new cases and 53,000 deaths projected in the US in 2024 (1). Colorectal cancer development is driven by a series of genetic mutations, such as those in APC, KRAS, TP53, and PIK3CA, among others. (2). APC is mutated at a very early stage and results in benign adenoma formation (2). The WT APC is required for a complex with axin that eventually leads to β-catenin’s phosphorylation by GSK3β and its subsequent degradation (2). When APC is inactivated by mutations, β-catenin is accumulated and translocated into the nucleus, where it interacts with the transcription factor TCF-4, and they both transcriptionally activate a variety of genes, especially those involved with cellular proliferation and survival (2). With the accumulation of other mutations in KRAS, PIK3CA, and TP53, the benign adenomas become malignant adenocarcinoma and eventually metastasize (2). Historically, Apc multiple intestinal neoplasia (Apc^Min) mice (3), which harbor an Apc nonsense mutation (4), are widely used to model colorectal tumorigenesis. However, most tumors developed in the Apc^Min mice only occur in the small intestines. While colon tumors in the context of Apc^Min can be induced using the bacterium enterotoxigenic Bacteroides fragilis (ETBF), it is unclear whether ETBF plays a causal role in human colorectal tumorigenesis. To circumvent this problem, Eric Fearon’s group developed a CDX2P-CreER^T2 transgenic mouse strain that conditionally deletes genes in the colon. Notably, the CDX2P-CreER^T2Apc^fl/fl mice develop adenomas in the colon, not in the small intestine (5).

Many genes, which are expressed in embryonic development and adult stem cells but inactivated in differentiated tissues, are reactivated in cancer cells. High mobility group A (HMGA1) is one of those genes. High mobility group (HMG) proteins, of which HMGA1 is a member, are the second-most abundant proteins in chromosomes, orchestrating chromatin remodeling processes and governing gene transcription in eukaryotic cells (6). In many cancer types, including colorectal cancer, HMGA1 is overexpressed (6). Further, APC loss promotes HMGA1 expression through the mobilization of β-catenin/TCF-4 transcriptional complex (7).

In this issue of the JCI, Luo et al. demonstrated that HMGA1 plays an important role in colon tumorigenesis (8). First, using the CDX2P-CreER^T2Apc^fl/fl mouse model, the authors showed that knockout of Hmga1 in the mice reduced tumor burden and extended their survival (8). Second, Hmga1 knockout in the context of Apc^Min with ETBF, reduced tumor number, regardless of whether the HMGA1 deficiency was global or specific to the intestinal epithelium (8). Notably, even heterozygous Hmga1 knockout reduced colon tumorigenesis in both mouse models (8).

The epithelia of the colon and small intestine are constantly renewed by the intestinal stem cells in crypts (9). In the small intestine, a pool of proliferative crypt-base columnar (CBC) cells that are marked by LGR5 is generally believed to be the intestinal stem cells (9). The LGR5⁺ stem cells divide every 24 hours and generate transit-amplifying cells (9), which migrate upward and differentiate into absorptive enterocytes, enteroendocrine cells, and goblet cells (9). These differentiated cells form the finger-like structure of the villus. Paneth cells escape this upward flow, migrate to the bottom of the crypt, and intermingle with LGR5⁺ stem cells (9). Notably, most recent studies showed that the stemness potential is also found in the intestinal crypt isthmus, which participates in intestinal homeostasis and regeneration (10, 11). Although the colon does not have villi, the crypt structure of the colon is similar to that of the small intestine. Notably, paneth cells are not detected in the colon, but it has been suggested that paneth-like cells are intermingled with the LGR5⁺ stem cells at the bottom of crypts. To interrogate how HMGA1 affects the cell composition in the colon, Luo and authors performed scRNA-seq in proximal colon crypt cells from CDX2P-CreER^T2Apc^fl/fl Hmga1^+/+ and CDX2P-CreER^T2Apc^fl/fl Hmga1^–/– mice. Given the role of HMGA1 in adult stem cells, it is not surprising that stem cell populations were decreased in the Hmga1-knockout colon crypts compared with those of Hmga1 WT mice (8). Paneth-like cells were also decreased in knockout colon crypts, which is consistent with a previous study by the same group showing that HMGA1 induces SOX9 gene expression, thereby promoting Paneth-like cell differentiation (12). However, the relevance of the Paneth-like cell in colon tumorigenesis is not clear. Luo and authors claimed that HMGA1 depletion had minimal effects on colon epithelial regeneration under homeostatic conditions, based on the observation that Hmga1 heterozygous–knockout mice had normal development and lifespans (8). This claim needs to be solidified by careful examination of intestines in mice with intestinal-specific knockout of Hmga1 at young and old ages.

Trajectory and cell state analyses showed that HMGA1 promotes an undifferentiated stem cell state. To identify the underlying molecular mechanisms by which HMGA1 maintains the intestinal stem cell state and promotes colon tumorigenesis, Luo and authors focused on ASCL2 based on their observations that ASCL2 positively correlated with HMGA1 expression in both mouse crypt cells and human colorectal cancer samples (8). The ASCL2 transcription factor acts as a Wnt-responsive switch to control stemness in the intestine (13). Luo and colleagues demonstrated that HMGA1 is directly bound to the ASCL2 promoter and activated ASCL2 expression in human colon cancer cells (Figure 1). Furthermore, overexpression of ASCL2 in HMGA1-knockdown CRC cells partially rescued the slow growth of the HMGA1-silenced cells. HMGA1 activated ASCL2 gene expression by increasing the activating histone marks (H3K4me3, H3K27Ac) and decreasing the repressive histone marker (H3K27me3), thereby opening the ASCL2 promotor region (8). However, how HMGA1 promotes the deposition of activating histone marks remains to be determined.

Figure 1

HMGA1 plays a pivotal role in colon tumorigenesis driven by the loss of APC. (A) APC loss results in β-catenin stabilization and nuclear translocation, thereby activating its target gene expression, including Ascl2. HMGA1 directly binds to the Ascl2 promotor, upregulates activating histone markers (H3K4me3 and H3K27Ac), decreases the repressive histone marker (H3K27me3), increases chromatin accessibility, and facilitates β-catenin–mediated expression of ASCL2. (B) In the context of APC loss, HMGA1 deficiency reduces ASCL2 expression and decreases colon tumorigenesis.

Besides the epithelia, lamina propria is the connective tissue layer containing blood vessels, lymphatics, and immune cells (14). Interestingly, the scRNA-seq analysis indicated that the quantity of CD4⁺ and CD8⁺ T cells was increased in the CDX2P-CreER^T2Apc^fl/fl Hmga1^–/– colon crypt cells compared with the WT Hmga1 counterpart (8). However, it remains to be determined if the increased T cell infiltration is caused by the loss of Hmga1 in the epithelial cells or T cells. Nonetheless, the gene signature enrichment analysis in the epithelial cells showed that the INF-α and INF-γ pathways were enriched, suggesting that loss of HMGA1 in the epithelial cells may affect the immune microenvironment in the colon and result in the increased T cell infiltration (8). The exact mechanisms warrant further investigation.

Luo and authors provided compelling evidence that HMGA1 plays a pivotal role in colon tumorigenesis driven by the loss of APC through regulating ASCL2 to promote an undifferentiated stem cell state (8). HMGA1 increases the accessibility of transcription factor ASCL2, a crucial regulator of stemness, thereby activating its transcription. This study suggests that HMGA1 is an epigenetic gatekeeper for the APC/β-catenin–regulated transcriptional network.

This work was supported by NIH grants R01CA196643, R01CA264320, R01CA260629, P50CA150964, and P30 CA043703 to ZW.

Address correspondence to: Zhenghe Wang, BRB731, 10900 Euclid Avenue, Cleveland, Ohio, 44106, USA. Phone: 216.368.0446; Email: zxw22@case.edu.

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2025, Wang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2025;135(3):e187442. https://doi.org/10.1172/JCI187442.

See the related article at HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis.

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