Preprogramming therapeutic response of PI3K/mTOR dual inhibitor via the regulation of EHMT2 and p27 in pancreatic cancer

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Title:	Preprogramming therapeutic response of PI3K/mTOR dual inhibitor via the regulation of EHMT2 and p27 in pancreatic cancer
Authors:	Tian, Yu-Feng Wang, Hui-Ching Luo, Chi-Wen Hung, Wen-Chun Lin, Yu-Han Chen, Tzu-Yi Li, Chien-Feng Lin, Chen-Yi Pan, Mei-Ren
Contributors:	Chi Mei Med Ctr, Dept Surg, Div Colorectal Surg Chia Nan Univ Pharm & Sci, Dept Hlth & Nutr Kaohsiung Med Univ, Coll Med, Grad Inst Clin Med Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Internal Med, Div Hematol & Oncol Chang Gung Mem Hosp, Kaohsiung Med Ctr, Div Cardiol Natl Hlth Res Inst, Natl Inst Canc Res Chi Mei Med Ctr, Dept Pathol Natl Hlth Res Inst, Natl Inst Canc Res Southern Taiwan Univ Sci & Technol, Dept Biotechnol Chi Mei Med Ctr, Dept Internal Med, Div Gastroenterol & Hepatol
Keywords:	EHMT2 SKP2 p27 pancreatic cancer cell cycle
Date:	2018
Issue Date:	2019-11-15 15:44:06 (UTC+8)
Publisher:	E-CENTURY PUBLISHING CORP
Abstract:	Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease, which is characterized by its high invasiveness, rapid progression, and profound resistance to therapy. Gemcitabine is the first-line treatment option for pancreatic cancer patients, but the overall survival is quite low. Therefore, it is an urgent issue to identify new molecules for improved therapies, with better efficacy and less toxicity. Our previous data indicated that Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) functions as a therapeutic target to override GEM resistance and promote metastasis in the treatment of pancreatic cancer. Here, we screened a small-molecule library of 143 protein kinase inhibitors, to verify cytotoxicity of different inhibitors in EHMT2-depleted cells. We determined that the EHMT2 plays a promising modulating role for targeted PI3K/mTOR inhibition. Our data revealed that EHMT2 down-regulates p27 expression, and this contributes to tumor growth. The depletion of EHMT2, ectopic expression of methyltransferase-dead EHMT2, or treatment with an EHMT2 inhibitor decreases H3K9 methylation of p27 promoter and induces G1 arrest in PANC-1 pancreatic cancer cells. Consistent with these findings, in vivo tumor xenograft models, primary tumors, and the Oncomine database utilizing bioinformatics approaches, also show a negative correlation between EHMT2 and p27. We further demonstrated that low EHMT2 elevated BEZ235 sensitivity through up-regulation of p27 in PDAC cells; high levels of SKP2 decrease BEZ235 responsiveness in PDAC cells. Altogether, our results suggest the EHMT2-p27 axis as a potential marker to modulate cell response to dual PI3K/mTOR inhibition, which might provide a strategy in personalized therapeutics for PDAC patients.
Relation:	Minerva Anestesiologica, v.8, n.9, pp.1812-1822
Appears in Collections:	[Dept. of Health and Nutrition (including master's program)] Periodical Articles

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