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

Surabhi Dangi-Garimella,Krishan Kumar,Vaibhav Sahai,Hidayatullah G Munshi,Kazumi Ebine,Edna Cukierman

doi:10.1371/journal.pone.0064566

Surabhi Dangi-Garimella, Krishan Kumar + Show 4 more

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https://doi.org/10.1371/journal.pone.0064566

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Journal: PloS one	Publication Date: May 16, 2013
Citations: 60	License type: CC0 1.0

Affiliation: Northwestern University, Jesse Brown VA Medical Center

Abstract

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.

Highlights

Despite tremendous efforts, the progress made in the treatment of pancreatic ductal adenocarcinoma (PDAC) has been frustratingly scant [1,2]
We showed that the chemo-protection was due to increased expression of high mobility group A2 (HMGA2) [6], an architectural protein involved in regulating the chromatin state [10]
Since histone acetyltransferases (HATs) have been linked with changes in the chromatin state and mediate the response to DNA damage [19,20,21,22,27,28], we examined whether fibrosis in human PDAC tumors was associated with changes in histone acetylation

Summary

Introduction

The progress made in the treatment of pancreatic ductal adenocarcinoma (PDAC) has been frustratingly scant [1,2]. PDAC continues to remain the fourth leading cause of cancer-related deaths in the US, with an ,80% one-year mortality for most patients [3] This lack of progress is in part due to the pronounced collagen-rich fibrotic reaction associated with PDAC tumors [4,5], which subsequently limits the delivery and efficacy of chemotherapy [6,7,8,9]. PDAC patients whose tumors demonstrated a low expression of histone H3 lysine 27 trimethylation (H3K27Me3) or histone H3 lysine 9 di-methylation (H3K9Me2), which are marks of closed chromatin (‘heterochromatin’) and gene repression [16,17,18], had significantly shorter overall survival than PDAC patients whose cancers displayed high histone H3K27Me3 or histone H3K9Me2 expression [14,15]. In contrast to histone methylation, which is associated with both gene activation and repression, histone acetylation has only been linked with gene activation associated with the euchromatin state [16,17,18]

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