Oncotarget

Research Papers:

The histone methyltransferase G9a as a therapeutic target to override gemcitabine resistance in pancreatic cancer

Mei-Ren Pan, Ming-Chuan Hsu, Chi-Wen Luo, Li-Tzong Chen, Yan-Shen Shan and Wen-Chun Hung _

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Oncotarget. 2016; 7:61136-61151. https://doi.org/10.18632/oncotarget.11256

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Abstract

Mei-Ren Pan1,2, Ming-Chuan Hsu3, Chi-Wen Luo4, Li-Tzong Chen3,5, Yan-Shen Shan6,7, Wen-Chun Hung3,8

1Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

2Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

3National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan

4Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan

5Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan

6Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan

7Department of Surgery, National Cheng Kung University Hospital, Tainan 704, Taiwan

8Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 704, Taiwan

Correspondence to:

Wen-Chun Hung, email: [email protected]

Keywords: lysine demethylase, drug resistance, interleukin-8, pancreatic stellate cell

Received: February 25, 2016     Accepted: July 27, 2016     Published: August 12, 2016

ABSTRACT

Gemcitabine (GEM) resistance is a critical issue for pancreatic cancer treatment. The involvement of epigenetic modification in GEM resistance is still unclear. We established a GEM-resistant subline PANC-1-R from the parental PANC-1 pancreatic cancer cells and found the elevation of various chromatin-modifying enzymes including G9a in GEM-resistant cells. Ectopic expression of G9a in PANC-1 cells increased GEM resistance while inactivation of G9a in PANC-1-R cells reduced it. Challenge of PANC-1 cells with GEM increased the expression of stemness markers including CD133, nestin and Lgr5 and promoted sphere forming activity suggesting chemotherapy enriched cancer cells with stem-like properties. Inhibition of G9a in PANC-1-R cells reduced stemness and invasiveness and sensitized the cells to GEM. We revealed interleukin-8 (IL-8) is a downstream effector of G9a to increase GEM resistance. G9a-overexpressing PANC-1-R cells exhibited autocrine IL-8/CXCR1/2 stimulation to increase GEM resistance which could be decreased by anti-IL-8 antibody and G9a inhibitor. IL-8 released by cancer cells also activated pancreatic stellate cell (PSC) to increase GEM resistance. In orthotopic animal model, GEM could not suppress tumor growth of PANC-1-R cells and eventually promoted tumor metastasis. Combination with G9a inhibitor and GEM reduced tumor growth, metastasis, IL-8 expression and PSC activation in animals. Finally, we showed that overexpression of G9a correlated with poor survival and early recurrence in pancreatic cancer patients. Collectively, our results suggest G9a is a therapeutic target to override GEM resistance in the treatment of pancreatic cancer.


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