Chromatin architecture protein HMGA2 promotes glioma malignancy via novel mechanism of IGFBP3 transcription inhibition.

Liang Zenghua, Qiao Lu, Ma Pengyi, Zhang Shanshan, Sun Cuiyun, Luo Wenjun, Yu Lin

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Cellular and Molecular Immunology and Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin 300070, China.

Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China.

Pathol Res Pract. 2025 Aug;272:156051. doi: 10.1016/j.prp.2025.156051. Epub 2025 May 27.

BACKGROUND

Glioma, the most prevalent primary brain tumor, is characterized by rapid proliferation, invasive growth patterns, and poor clinical outcomes. This study investigates the expression and clinical significance of chromatin architecture protein high mobility group AT-hook 2 (HMGA2) in glioma, aiming to identify potential prognostic biomarkers and therapeutic targets.

METHODS

The expression of HMGA2 in different grades glioma samples was analyzed by immunohistochemistry (IHC). The functions of HMGA2 in glioma cells were identified by migration, invasion, proliferation and orthotopic tumor transplantation assays. The downstream genes of HMGA2 were screened by RNA-Seq. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR), electrophoretic mobility shift assay (EMSA) and chromosome conformation capture assay (3 C) were used to analyze the downstream mechanism of HMGA2 in glioma cells.

RESULTS

We demonstrated a positive correlation between HMGA2 expression levels and glioma malignancy grade through IHC analysis. Multivariate COX regression analysis further established HMGA2 as an independent prognostic factor in glioma. Our functional studies revealed that HMGA2 significantly enhances the migration, invasion, and proliferation capabilities of glioblastoma (GBM) cells. Mechanistically, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a novel downstream target of HMGA2. HMGA2 mediates transcriptional repression of IGFBP3 through disruption of promoter-enhancer interactions, leading to subsequent activation of the PI3K/Akt signaling pathway and promotion of malignant phenotypes in GBM.

CONCLUSION

We confirmed a novel chromatin conformation-mediated transcriptional repression mechanism of HMGA2. By regulating IGFBP3 expression and modulating the PI3K/Akt pathway, HMGA2 emerges as a promising prognostic biomarker and potential therapeutic target for glioma patients.