Preprogramming therapeutic response of PI3K/mTOR dual inhibitor via the regulation of EHMT2 and p27 in pancreatic cancer.
Preprogramming therapeutic response of PI3K/mTOR dual inhibitor via the regulation of EHMT2 and p27 in pancreatic cancer.
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发表时间：
2018
影响因子：
5.3
通讯作者：
Yu-Feng Tian;Hui-Ching Wang;C. Luo;W. Hung;Yu-Han Lin;Tzu-Yi Chen;Chien-Feng Li;Chen-Yi Lin
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作者：
Yu-Feng Tian;Hui-Ching Wang;C. Luo;W. Hung;Yu-Han Lin;Tzu-Yi Chen;Chien-Feng Li;Chen-Yi Lin
胰腺导管腺癌是一种侵袭性较强的疾病，具有侵袭性强、进展快、对治疗的抵抗力强等特点。吉西他滨是胰腺癌患者的一线治疗选择，但总体存活率相当低。因此，寻找新的分子来改进治疗方法，以获得更好的疗效和更低的毒性，是一个紧迫的问题。我们以前的资料表明，常染性组蛋白赖氨酸N-甲基转移酶2(EHMT2)在胰腺癌的治疗中可以作为一个治疗靶点，以克服GEM耐药和促进转移。在这里，我们筛选了一个由143种蛋白激酶抑制剂组成的小分子文库，以验证不同抑制剂对EHMT2耗竭细胞的细胞毒性。我们确定EHMT2对靶向抑制PI3K/mTOR具有很好的调控作用。我们的数据显示，EHMT2下调p27的表达，这有助于肿瘤的生长。EHMT2缺失、甲基转移酶死亡的EHMT2异位表达或EHMT2抑制剂处理可降低p27启动子H3K9甲基化，并诱导PANC-1胰腺癌细胞G1期停滞。与这些发现一致的是，体内肿瘤异种移植模型、原发肿瘤和利用生物信息学方法建立的肿瘤数据库也显示EHMT2和p27之间存在负相关。我们进一步证明，低EHMT2通过上调PDAC细胞中p27的表达来提高BEZ235的敏感性；高水平的Skp2降低了PDAC细胞中BEZ235的反应性。总之，我们的结果提示，EHMT2-p27轴可以作为一个潜在的标记物来调节细胞对双重PI3K/mTOR抑制的反应，这可能为PDAC患者的个性化治疗提供一种策略。
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.