Abstract
To identify the function and underlying mechanisms of HMGA2 on the prognosis and invasion of gliomas, HMGA2 was detected by immunohistochemistry. The Kaplan‐Meier and Cox's regression analysis results showed that higher HMGA2 level predicted the poorer outcomes of glioma patients. ChIP‐qPCR, DNA electrophoretic mobility shift assay, chromosome conformation capture, and co‐immunoprecipitation were applied to identify HMGA2‐activated target sites, which were further verified by mRNA and protein expression detection. Transwell and orthotopic implantation were used to investigate the roles of HMGA2 in glioma cells. HMGA2 shRNA transfection inhibited glioblastoma invasion. Mechanistically, we first discovered that HMGA2, together with GCN5, facilitated the invasion of glioma cells via inducing chromatin conformational remodeling of the MMP2 gene promoter and epigenetically activating MMP2 gene transcription. Our results indicated that HMGA2, as a novel GCN5 recognition partner and histone acetylation modulator, may be novel prognostic indicator and promising glioma treatment target.
Highlights
HMGA2-coding sequence (HMGA2) overexpression has been detected in different malignant tissues,[27,28,29,30,31,32] the oncogenic mechanism and clinical relevance of HMGA2 in gliomas remained unclear
Our results showed increased expression of the HMGA2 protein in the majority of both GBM and World Health Organization (WHO) grade I-III glioma tumors by IHC using a cohort of 147 grade I-IV gliomas compared to 20 normal brain samples
Our results showed that the HMGA2 level was remarkably and positively correlated with glioma grade in our 147 glioma specimens, indicating that HMGA2 may act as a promising biomarker to distinguish the WHO grades of glioma
Summary
Gliomas have the highest incidence among primary brain tumors.[1,2] Among high-grade glioma, glioblastoma (GBM) exhibits especially lethal and poor prognosis.[3,4] Significant intragroup variations in the prognosis among glioma patients interfere with the clinical diagnosis.[5,6,7] The current glioma histopathologic diagnosis criteria, which are widely used, are unable to comprehensively evaluate the patients’ status and estimate their survival.[8,9,10] Based on our understanding of the molecular and genetic changes in gliomas, we explore new diagnostic markers, prognostic evaluation factors, and therapy approaches for gliomas. The HMGA2/GCN5 complex bound the AT-r ich region of DNA and catalyzed histone. HMGA2 induced a chromatin conformational change in the promoter region of matrix metalloproteinase 2 (MMP2), a well-documented extracellular matrix regulator[20,21] and invasion factor.[21,22,23] HMGA2 recruited the enhancer complex to transcription start site (TSS) of MMP2 and promoted the gene expression and invasion phenotype of GBM cells. U87MG cells were obtained from the American Type Culture Collection (ATCC, Manassas, USA) in July 2017. MycoProbe Mycoplasma Detection Kit was used to detect mycoplasma contamination (R&D, Minneapolis, USA), and the latest test was performed on 23 November 2017
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