Suppression of Nonhomologous End Joining Repair by Overexpression of HMGA2

Li, Angela Y J; Boo, Lee Ming; Wang, Shih Ya; Lin, H. Helen; Wang, Clay C. C.; Yen, Yun; Chen, Benjamin P.C.; Chen, David J.; Ann, David K.

doi:10.1158/0008-5472.can-08-4833

Cited by 73 publications

(73 citation statements)

References 44 publications

(55 reference statements)

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“…23 Finally, the HMGA2 gene is involved in modulation of DNA repair, and overexpression of HMGA2 leads to the promotion of genome instability and tumorigenesis. 39,40 In conclusion, our results indicate correlation between expression of several miRNAs and somatic mutations in lung adenocarcinomas. These miRNAs may have a role in cancer development and may be associated with more aggressive behavior of some tumor types.…”

Section: Discussionsupporting

confidence: 58%

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

et al. 2010

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MicroRNA (miRNA) expression is deregulated in lung cancer, and some miRNAs are associated with poor prognosis and survival. In this study, we investigated the miRNA expression in lung adenocarcinomas with different oncogenic mutations, including EGFR-positive, KRAS-positive and EGFR/KRAS-negative tumors. The expression of 319 miRNAs was evaluated by Exiqon/Luminex microarray, and expression of individual miRNAs was validated by individual RT-PCR assays (Applied Biosystems). Overall, miRNA expression was similar among three mutationally different groups with most upregulated miRNAs being miR-20a, miR-328, miR-34c and miR-18b and most downregulated miRNAs being miR-32, miR-137 and miR-342. Four miRNAs (miR-155, miR-25, miR-495 and miR-7g) were expressed differently among these tumors. miR-155 was upregulated only in EGFR/KRAS-negative group, miR-25 was upregulated only in EGFR-positive group and miR-495 was upregulated only in KRAS-positive adenocarcinomas. In opposite, let-7g was downregulated in all three groups, with more significant downregulation in EGFR/KRASnegative adenocarcinomas. Principal component analysis (PCA) revealed significant correlation between miRNA expression patterns and somatic mutations. In this study, we demonstrated that despite the similarity in miRNA expression among lung adenocarcinomas with different somatic mutations, some miRNAs showed unique expression patterns, which were in strong correlation with the mutation type, suggesting different carcinogenic pathway for these tumors. These miRNAs can be further explored for their diagnostic and prognostic use.

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Section: Discussionsupporting

confidence: 58%

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

et al. 2010

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“…The oncogenic properties of HMGA2 are known to be involved in tumor cell differentiation, transformation (16,17), aggressive tumor growth (24,34), early metastasis (35,36), and DNA damage response (37). HMGA2 has also been found to participate in the epithelial-to-mesenchymal transition, an essential process important to both normal development and tumor progression (38,39).…”

Section: Discussionmentioning

confidence: 99%

Frequent Overexpression of HMGA2 in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with let-7a3/let-7b miRNA

Zhang

Gao

et al. 2014

Clinical Cancer Research

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Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive pediatric malignancies characterized by biallelic inactivation of the SMARCB1 tumor suppressor gene. We searched for novel genomic aberrations by investigating the copy number and expression alterations of let-7a3/let-7b micro-RNA (miRNA) and correlated these with expression of high-mobility group AT-hook 2 (HMGA2) oncoprotein, a target of let-7 miRNA family, in 18 AT/RT samples to elucidate potential roles of HMGA2 in the pathogenesis of AT/RT.Experimental Design: Genomic aberrations, let-7a3/let-7b miRNA and HMGA2 expression in AT/RT tissues were identified using quantitative PCR, reverse transcription PCR (RT-PCR), and immunohistochemistry. The impact of let-7b miRNA on HMGA2 expression and the malignant potential of human rhabdoid tumor cell G401 (SMARCB1 À/À ) were investigated by antisense inhibition and ectopic overexpression studies.Results: The copy number of let-7a3/let-7b miRNA was substantially decreased in 4 of 11 AT/RT samples. A significantly inverse correlation between let-7a3/let-7b miRNA expression and HMGA2 mRNA expression was observed in AT/RT tissues (R ¼ À0.34; P < 0.05). Immunohistochemistry analysis demonstrated that HMGA2 was highly overexpressed in 83.3% (15 of 18) of AT/RT tissues. Restoration of let-7 miRNA or knockdown of HMGA2 expression significantly suppressed proliferation and colony formation, and almost abolished the invasive potential of G401 cells.Conclusion: Reduction of let-7a3/let-7b miRNA may be one of mechanisms leading to overexpression of HMGA2 in AT/RT tissues. HMGA2 oncoprotein plays critical roles in the pathogenesis of AT/RT development; and reconstitution of let-7 miRNA or knockdown of HMGA2 oncoprotein may provide a novel therapeutic strategy for the treatment of patients with AT/RT.

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“…This perspective might explain the fact that proteins and histone modifications that were initially characterized during DNA repair also play a role during transcription, recombination, and replication. In line with this hypothesis, a common characteristic between HMGA2 transgenic [41], ATM −/− [42], and H2AX −/− [43] mice is genomic instability. In addition, DNA repair-linked histone modifications, H3K56ac and H2Bub1 [44], have been related to transcription initiation [45].…”

Section: Discussionmentioning

confidence: 72%

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

et al. 2015

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The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFβ1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome.

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Suppression of Nonhomologous End Joining Repair by Overexpression of HMGA2

Cited by 73 publications

References 44 publications

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

Frequent Overexpression of HMGA2 in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with let-7a3/let-7b miRNA

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

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