PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer
PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer
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PES1 通过增加胰腺癌中 c-Myc 的表达来促进 BET 抑制剂耐药性和细胞增殖
DOI：
10.1186/s13046-019-1466-7
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发表时间：
2019-11-12
影响因子：
11.3
通讯作者：
Liu, Tao
中科院分区：
文献类型：
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作者：
Jin, Xin;Fang, Rui;Liu, Tao
背景在多种类型的恶性肿瘤中，过度表达的PES1可促进癌变。然而，PES1在胰腺癌中的生物学作用和临床意义尚不清楚。方法采用Western Blotting分析、RT-qPCR分析、组织芯片免疫组化（IHC）分析和GEPIA网络工具检测胰腺癌细胞系和胰腺癌患者标本中PES1的表达水平。采用MTS法、集落形成法和异种移植肿瘤法评价胰腺癌细胞的肿瘤生长能力。结果PES1在胰腺癌组织中表达异常增高，导致胰腺癌患者预后不良。我们还发现，在胰腺癌中，PES1负责促进细胞生长，并有助于溴域结构域和癌细胞对外端（BET）抑制剂的抗性。此外，我们发现PES1与BRD4相互作用增强c-Myc表达，这是胰腺癌癌细胞对BET抑制剂耐药的主要原因。最后，CDK5抑制剂被证明可以破坏胰腺癌细胞中PES1的稳定性，并克服癌细胞对BET抑制剂的耐药性。结论PES1可能是胰腺癌肿瘤生长的促进因子之一，是胰腺癌预后相关蛋白。用CDK5抑制剂靶向PES1可能有助于克服胰腺癌细胞对BET抑制剂的耐药性。
AbstractsBackgroundOverexpressed PES1 promotes carcinogenesis in various types of malignant tumors. However, the biological role and clinical significance of PES1 in pancreatic cancer are still unexplored.MethodsThe expression level of PES1 in pancreatic cancer cell lines and pancreatic cancer patient samples was determined using Western Blotting analysis, RT-qPCR analysis, immunohistochemical (IHC) analysis of tissue microarray, and the GEPIA web tool. MTS assay, colony formation assay, and xenograft tumor assay were used to evaluate the tumor growth ability of pancreatic cancer cells.ResultsWe established that the expression of PES1 was abnormally increased in pancreatic cancer tissues and led to poor prognosis of pancreatic cancer patients. We also found that PES1 was responsible for promoting cell growth and contributed to bromodomain and cancer cell resistance to extra-terminal (BET) inhibitors in pancreatic cancer. Furthermore, we showed that PES1 interacted with BRD4 to enhance c-Myc expression, which is the primary cause of cancer cell resistance to BET inhibitors in pancreatic cancer. Finally, CDK5 inhibitors were proven to destabilize PES1 and overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.ConclusionsWe have shown that PES1 could be one of the promoting factors of tumor growth and a prognosis-related protein of pancreatic cancer. Targeting PES1 with CDK5 inhibitors might help overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.