High-Mobility Group A2 Protein Modulates <i>hTERT</i> Transcription To Promote Tumorigenesis

Li, Angela Ying Jian; Lin, H. Helen; Kuo, Ching‐Ying; Shih, Hsiu Ming; Wang, Clay Chia Chun; Yen, Yun; Ann, David K.

doi:10.1128/mcb.05447-11

Cited by 47 publications

(38 citation statements)

References 64 publications

(88 reference statements)

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“…Human let-7 miRNA (LentimiRa-GFP-hsa-let-7 Vector, mh10004) and HMGA2 short hairpin RNA (shRNA) in piLenti-siRNA-GFP (I009810b) were purchased from Applied Biological Materials Inc.. Lentiviral production in human embryonic kidney (HEK) 293T cells was as we previously described (21). For stable infection, 8 Â 10 4 cells were plated in each well of 6-well plates.…”

Section: Immunohistochemistry and Western Blotmentioning

confidence: 99%

“…As an important regulator of cell growth, differentiation, apoptosis, and transformation, HMGA2 interacts with many different transcription factors such as E2F1 to influence the expression of numerous genes (20). Recently, we also found that HMGA2 may promote tumorigenesis through modulation of human telomerase reverse transcriptase (hTERT) transcriptional activity (21). Multiple studies have identified a negative correlation between reduced expression of the let-7 miRNA family and overexpression of Ras/HMGA2 in various human cancer tissues (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Immunohistochemistry and Western Blotmentioning

confidence: 99%

Section: Introductionmentioning

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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“…S5 A and B). Previous work showed that Hmga2 overexpression displaces histone deacetylase (HDAC) from chromatin and causes increased acetylation of histone H3 on target gene promoters (22,35). We performed immunoblotting and immunofluorescence assays to characterize the epigenetic changes induced by Hmga2 overexpression and found a notable increase in histone acetylation at H3 lysine 9/14 in Hmga2-UGSM cells (Fig.…”

Section: Sustained Overexpression Of Hmga2 In Stromal Cells Is Requirmentioning

confidence: 85%

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Zong

Huang²,

Sankarasharma³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AThook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/β-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

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“…This is intriguing given the propensity of these cells for escape from telomere-driven crisis and cellular transformation via telomerase reactivation (Jones et al 2014). Conjointly, we sequence-verified fusion junctions within the HMGA2 (Li et al 2011) gene (Chr12q14.3) and Chr3p21.31 region implicated in the regulation of telomerase activity ( Fig. 3C; Cuthbert et al 1999) from LIG3 −/− and PARP1 −/− samples.…”

Section: A-and C-nhej Of Dysfunctional Human Telomeresmentioning

confidence: 85%

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 doubleknockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.

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High-Mobility Group A2 Protein Modulates hTERT Transcription To Promote Tumorigenesis

Cited by 47 publications

References 64 publications

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

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

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

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