Chromatin Immunoprecipitation to Analyze DNA Binding Sites of HMGA2

Winter, Nina; Nimzyk, Rolf; Bösche, Carolin; Meyer, Anke; Bullerdiek, Jörn

doi:10.1371/journal.pone.0018837

Cited by 33 publications

(21 citation statements)

References 43 publications

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“…Because HMGA2 is a genomic architectural factor, we do not exclude the possibility that HMGA2 might be able to regulate TET1 expression by direct binding to the TET1 promoter or by alteration of its chromatin structure. Nonetheless, a recent investigation of HMGA2 binding sites in HCT116 cells that highly express HMGA2 protein showed only 49 binding sites (35). None of them are even close to the genomic locus of TET1 gene.…”

Section: Discussionmentioning

confidence: 95%

HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis

Sun

Song²,

Huang

et al. 2013

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

244

232

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The ten-eleven translocation (TET) family of methylcytosine dioxygenases initiates demethylation of DNA and is associated with tumorigenesis in many cancers; however, the mechanism is mostly unknown. Here we identify upstream activators and downstream effectors of TET1 in breast cancer using human breast cancer cells and a genetically engineered mouse model. We show that depleting the architectural transcription factor high mobility group AThook 2 (HMGA2) induces TET1. TET1 binds and demethylates its own promoter and the promoter of homeobox A (HOXA) genes, enhancing its own expression and stimulating expression of HOXA genes including HOXA7 and HOXA9. Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts. The genes comprising the HMGA2-TET1-HOXA9 pathway are coordinately regulated in breast cancer and together encompass a prognostic signature for patient survival. These results implicate the HMGA2-TET1-HOX signaling pathway in the epigenetic regulation of human breast cancer and highlight the importance of targeting methylation in specific subpopulations as a potential therapeutic strategy. E pigenetic changes play an important role in cancer progression as well as development (1). Recent studies indicate that DNA demethylation can be catalyzed by a class of methylcytosine dioxygenases termed the ten-eleven translocation (TET) family (2-5). TET1 promotes DNA demethylation by catalyzing conversion of 5-methylcytosine (5mC) primarily to 5-hydroxymethylcytosine (5hmC) as well as 5-formylcytosine or 5-carboxylcytosine (3, 5). The modified cytosines are then removed through active or passive mechanisms (2-6). While TET1 is highly expressed in embryonic stem (ES) cells (5, 7-10), loss of TET1 protein and decreased 5hmC levels have been recently shown in solid tumors relative to normal epithelial cells (2,(11)(12)(13)(14). However, the mechanism by which TET1 is suppressed in solid tumors has not been identified. Furthermore, the downstream targets by which TET1 regulates growth and metastasis in cancer are largely unknown.High mobility group AT-hook 2 (HMGA2), a chromatinremodeling factor (15), binds to AT-rich regions in DNA, altering chromatin architecture to either promote or inhibit the action of transcriptional enhancers. HMGA2 is highly expressed in ES cells but is generally low or lacking in normal somatic cells. Interestingly, HMGA2 is highly expressed in most malignant epithelial tumors, including breast (16), pancreas (17), oral squamous cell carcinoma (18), and non-small-cell lung cancer (19). HMGA2 overexpression in transgenic mice causes tumor formation, whereas Hmga2-knockout mice have a pygmy phenotype indicative of a growth defect (20). We have reported that HMGA2 promotes tumor invasion and metastasis in breast cancer in part through regulation of prometastatic genes, including Snail, osteopontin, and CXCR4 (21,22).To systematically identify critical downstream mediators of HMGA2 that regulate invasion and metastasis, we performed gene expression array analysis by knocki...

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Section: Discussionmentioning

confidence: 95%

HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis

Sun

Song²,

Huang

et al. 2013

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

244

232

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“…Fold enrichment method: 47 the ChIP signals are divided by the no-antibody signals, representing the ChIP signal as the fold increase in signal relative to the background signal.…”

Section: Methodsmentioning

confidence: 99%

ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence

Fausti¹,

Agostino²,

Cioce³

et al. 2013

Cell Death Differ

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Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.

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“…[20][21][22][23][24] A list of some HMGA-binding proteins is shown in Table 1. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] This list only includes proteins of which a cancer-related function is known. Interactions such as these, as well as post-translational modifications discussed elsewhere in this issue, frequently dictate how HMGA proteins behave.…”

Section: Introductionmentioning

confidence: 99%

High mobility group A-interacting proteins in cancer: focus on chromobox protein homolog 7, homeodomain interacting protein kinase 2 and PATZ

Fedele

Pierantoni

Pallante

2012

J Nucleic Acids Invest

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The High Mobility Group A (HMGA) proteins, a family of DNA architectural factors, by interacting with different proteins play crucial roles in neoplastic transformation of a wide range of tissues. Therefore, the search for HMGA-interacting partners was carried out by several laboratories in order to investigate the mechanisms underlying HMGA-dependent tumorigenesis. Three of the several HMGAbinding proteins are discussed in this review. These are the Chromobox family protein (chromobox protein homolog 7, CBX7), the homeodomain interacting protein kinase 2 (HIPK2) and the POZ/domain and Kruppel zinc finger family member, PATZ. All of them play a critical role in tumorigenesis, and may also be independent markers of cancer. Their activities are linked to cell cycle, apoptosis and senescence. In this review, we discuss the properties of each protein, including their effect on HMGA1 functions, and propose a model accounting for how their activities might be coordinated.

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Chromatin Immunoprecipitation to Analyze DNA Binding Sites of HMGA2

Cited by 33 publications

References 43 publications

HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis

HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis

ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence

High mobility group A-interacting proteins in cancer: focus on chromobox protein homolog 7, homeodomain interacting protein kinase 2 and PATZ

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