Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells

Zha, Lang; Wang, Ziwei; Tang, Weixue; Zhang, Neng; Liao, Gang; Huang, Zhen

doi:10.1007/s11010-012-1224-z

Cited by 29 publications

(25 citation statements)

References 27 publications

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“…Although we did not examine whether HMGA2 directly binds to HAT promoters to regulate expression, HMGA2, by acting as a global chromatin switch, has been shown to regulate >1,000 genes [31]. Some of these genes are regulated by HMGA2 by directly binding to the promoter sequences.…”

Section: Discussionmentioning

confidence: 98%

Three-Dimensional Collagen I Promotes Gemcitabine Resistance In Vitro in Pancreatic Cancer Cells through HMGA2-Dependent Histone Acetyltransferase Expression

et al. 2013

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Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have previously shown that PDAC cells are resistant to gemcitabine chemotherapy in the collagen microenvironment because of increased expression of the chromatin remodeling protein high mobility group A2 (HMGA2). We have now found that human PDAC tumors display higher levels of histone H3K9 and H3K27 acetylation in fibrotic regions. We show that relative to cells grown on tissue culture plastic, PDAC cells grown in three-dimensional collagen gels demonstrate increased histone H3K9 and H3K27 acetylation, along with increased expression of p300, PCAF and GCN5 histone acetyltransferases (HATs). Knocking down HMGA2 attenuates the effect of collagen on histone H3K9 and H3K27 acetylation and on collagen-induced p300, PCAF and GCN5 expression. We also show that human PDAC tumors with HMGA2 demonstrate increased histone H3K9 and H3K27 acetylation. Additionally, we show that cells in three-dimensional collagen gels demonstrate increased protection against gemcitabine. Significantly, down-regulation of HMGA2 or p300, PCAF and GCN5 HATs sensitizes the cells to gemcitabine in three-dimensional collagen. Overall, our results increase our understanding of how the collagen microenvironment contributes to chemo-resistance in vitro and identify HATs as potential therapeutic targets against this deadly cancer.

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Section: Discussionmentioning

confidence: 98%

Three-Dimensional Collagen I Promotes Gemcitabine Resistance In Vitro in Pancreatic Cancer Cells through HMGA2-Dependent Histone Acetyltransferase Expression

et al. 2013

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“…It is reasonable to propose that HMGA2 promotes VM formation in GC by regulating VE-cadherin. A computational analysis predicted that HMGA2 can target the promoter of Twist1 39 . It is known that Twist1 opens nuclear membrane pores with the help of an accessory protein and enters the nucleus to regulate the transcription of downstream genes that are involved in the process of VM 40 , and we have previously reported that Twist1 facilitates VM by modulating the promoter of VE-cadherin in hepatocellular carcinoma 30 .…”

Section: Discussionmentioning

confidence: 99%

HMGA2 promotes vasculogenic mimicry and tumor aggressiveness by upregulating Twist1 in gastric carcinoma

Sun

et al. 2017

Sci Rep

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High mobility group protein A2 (HMGA2) is a transcription factor that plays an important role in the invasion and metastasis of gastric carcinoma (GC). The term vasculogenic mimicry (VM) refers to the unique ability of aggressive tumour cells to mimic the pattern of embryonic vasculogenic networks. However, the relationship between HMGA2 and VM formation remains unclear. In the present study, we examined concomitant HMGA2 expression and VM in 228 human GC samples and 4 GC cell lines. Our data indicate that HMGA2 is not only significantly associated with VM formation but also influences the prognosis of patients with gastric carcinoma. Overexpression of HMGA2 significantly increased cell motility, invasiveness, and VM formation both in vitro and in vivo. A luciferase reporter assay, Co-IP and ChIP demonstrated that HMGA2 induced the expression of Twist1 and VE-cadherin by binding to the Twist1 promoter. Moreover, we observed a decrease in VE-cadherin following Twist1 knockdown in cells overexpressing HMGA2. This study indicates that HMGA2 promotes VM in GC via Twist1-VE-cadherin signalling and influences the prognosis of patients with GC.

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“…Moreover, HMGA2 overexpression can partially reverse the repressive effects of JQ1 on c-MYC and/or FOSL1 . Given that HMGA2 can act as a global chromatin switch (47), it is also possible that the ability of HMGA2 to counteract JQ1 may be through its effect on global changes in gene expression rather than modulation of c-MYC and/or FOSL1. Indeed, it has been shown that HMGA2 can regulate > 1,000 genes, either directly by binding to promoter sequences or indirectly through activation of signaling pathways (47, 48).…”

Section: Discussionmentioning

confidence: 99%

“…Given that HMGA2 can act as a global chromatin switch (47), it is also possible that the ability of HMGA2 to counteract JQ1 may be through its effect on global changes in gene expression rather than modulation of c-MYC and/or FOSL1. Indeed, it has been shown that HMGA2 can regulate > 1,000 genes, either directly by binding to promoter sequences or indirectly through activation of signaling pathways (47, 48). Although it is beyond the scope of this study, we plan in future studies to examine the effect of HMGA2 overexpression on changes in global gene expression following JQ1 treatment.…”

Section: Discussionmentioning

confidence: 99%

BET Bromodomain Inhibitors Block Growth of Pancreatic Cancer Cells in Three-Dimensional Collagen

Sahai¹,

Kumar

Knab

et al. 2014

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) is associated with pronounced fibrosis that contributes to chemoresistance, in part, through increased histone acetylation. Since bromodomain (BRD) and extra terminal domain (BET) proteins are ‘readers’ of histone acetylation marks, we targeted BET proteins in PDAC cells grown in three-dimensional collagen. We show that treatment with BET inhibitors decreases growth of PDAC cells (AsPC1, CD18 and Panc1) in collagen. Transfection with siRNA against BRD4, which is increased in human PDAC tumors, also decreases growth of PDAC cells. BET inhibitors additionally decrease growth in collagen of PDAC cells that have undergone epithelial-to-mesenchymal transition or have become resistant to chemotherapy. Although BET inhibitors and BRD4 siRNA repress c-MYC only in AsPC1 and CD18 cells, downregulating c-MYC decreases growth of all three PDAC cell lines in collagen. FOSL1, which is also targeted by BET inhibitors and BRD4 siRNA in AsPC1, CD18 and Panc1 cells, additionally regulates growth of all three PDAC cell lines in collagen. BET inhibitors and BRD4 siRNA repress HMGA2, an architectural protein that modulates chromatin state and also contributes to chemoresistance, in PDAC cells grown in collagen. Importantly, we show that there is a statistically significant correlation between BRD4 and HMGA2 in human PDAC tumors. Significantly, overexpression of HMGA2 partially mitigates the effect of BET inhibitors on growth and c-MYC and/or FOSL1 expression in collagen. Overall, these results demonstrate that BET inhibitors block growth of PDAC cells in collagen and that BET proteins may be potential targets for the treatment of pancreatic cancer.

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Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells

Cited by 29 publications

References 27 publications

Three-Dimensional Collagen I Promotes Gemcitabine Resistance In Vitro in Pancreatic Cancer Cells through HMGA2-Dependent Histone Acetyltransferase Expression

Three-Dimensional Collagen I Promotes Gemcitabine Resistance In Vitro in Pancreatic Cancer Cells through HMGA2-Dependent Histone Acetyltransferase Expression

HMGA2 promotes vasculogenic mimicry and tumor aggressiveness by upregulating Twist1 in gastric carcinoma

BET Bromodomain Inhibitors Block Growth of Pancreatic Cancer Cells in Three-Dimensional Collagen

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