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

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.

• Authors: Mei-Ren Pan, Ming-Chuan Hsu, Chi-Wen Luo, Li-Tzong Chen, Yan-Shen Shan, Wen-Chun Hung
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 38 Pg. 61136-61151 (Sep 20 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27531902 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• CXCL8 protein, human
• Histocompatibility Antigens
• Interleukin-8
• RNA, Small Interfering
• Receptors, Interleukin-8A
• Deoxycytidine
• Histone Demethylases
• EHMT2 protein, human
• Histone-Lysine N-Methyltransferase
• Gemcitabine

Topics

• Aged
• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Cell Movement
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm
• Extracellular Matrix (metabolism)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Histocompatibility Antigens (metabolism)
• Histone Demethylases (metabolism)
• Histone-Lysine N-Methyltransferase (metabolism)
• Humans
• Interleukin-8 (metabolism)
• Male
• Mice
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplastic Stem Cells (metabolism)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Pancreatic Stellate Cells (metabolism)
• RNA, Small Interfering (metabolism)
• Receptors, Interleukin-8A (metabolism)
• Gemcitabine