TET1 downregulates epithelial-mesenchymal transition and chemoresistance in PDAC by demethylating CHL1 to inhibit the Hedgehog signaling pathway
TET1 downregulates epithelial-mesenchymal transition and chemoresistance in PDAC by demethylating CHL1 to inhibit the Hedgehog signaling pathway
复制标题
TET1 通过去甲基化 CHL1 抑制 Hedgehog 信号通路，下调 PDAC 中的上皮间质转化和化疗耐药性
DOI：
10.1038/s41388-020-01407-8
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发表时间：
2020-08-04
期刊：
影响因子：
8
通讯作者：
Liu, Liang
中科院分区：
文献类型：
--
作者：
Li, Hao;Jiang, Wang;Liu, Liang
化疗耐药性是延长胰腺导管腺癌（PDAC）患者生存期的主要障碍。TET 1被认为是促进癌症耐药性的最重要的表观遗传修饰酶。然而，TET 1在PDAC中的化学抗性机制尚不清楚。本研究旨在确定TET 1在PDAC化疗耐药性中的作用。在体外和体内研究PDAC中TET 1相关的化疗耐药性。应用组织芯片技术分析228例PDAC患者TET 1基因表达的临床意义。我们发现TET 1的下调是由其启动子的高甲基化引起的，并与PDAC患者的生存率低相关。通过沉默或过表达TET 1进行的体外和体内功能研究表明，TET 1能够抑制上皮-间质转化（EMT）并使PDAC细胞对5 FU和吉西他滨敏感。然后利用RNA-seq、全基因组亚硫酸氢盐测序（WGBS）和ChIP-seq对TET 1相关通路进行了研究，发现TET 1通过结合CHL 1启动子并使其去甲基化，从而抑制Hedgehog通路，促进CHL 1的转录。此外，通过CHL 1过表达或Hedgehog通路抑制剂GDC-0449抑制Hedgehog信号传导，逆转了TET 1沉默诱导的化学抗性。关于临床意义，我们发现TET 1和CHL 1高表达预示可切除PDAC患者的预后更好。总之，我们证明TET 1通过下调CHL 1相关的Hedgehog信号通路逆转PDAC中的化学抗性。TET 1和CHL 1高表达的PDAC患者预后较好。
Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.