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TET1 downregulates epithelial-mesenchymal transition and chemoresistance in PDAC by demethylating CHL1 to inhibit the Hedgehog signaling pathway.
Li, Hao; Jiang, Wang; Liu, Xue-Ni; Yuan, Li-Yun; Li, Tian-Jiao; Li, Shuo; Xu, Shuai-Shuai; Zhang, Wu-Hu; Gao, He-Li; Han, Xuan; Wang, Wen-Quan; Wu, Chun-Tao; Yu, Xian-Jun; Xu, Hua-Xiang; Liu, Liang.
Afiliación
  • Li H; Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China.
  • Jiang W; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • Liu XN; Shanghai Pancreatic Cancer Institute, Shanghai, China.
  • Yuan LY; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
  • Li TJ; Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China.
  • Li S; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • Xu SS; Shanghai Pancreatic Cancer Institute, Shanghai, China.
  • Zhang WH; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
  • Gao HL; Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Han X; Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • Wang WQ; Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China.
  • Wu CT; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • Yu XJ; Shanghai Pancreatic Cancer Institute, Shanghai, China.
  • Xu HX; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
  • Liu L; Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China.
Oncogene ; 39(36): 5825-5838, 2020 09.
Article en En | MEDLINE | ID: mdl-32753651
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Moléculas de Adhesión Celular / Proteínas Proto-Oncogénicas / Resistencia a Antineoplásicos / Carcinoma Ductal Pancreático / Proteínas Hedgehog / Transición Epitelial-Mesenquimal / Oxigenasas de Función Mixta Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Moléculas de Adhesión Celular / Proteínas Proto-Oncogénicas / Resistencia a Antineoplásicos / Carcinoma Ductal Pancreático / Proteínas Hedgehog / Transición Epitelial-Mesenquimal / Oxigenasas de Función Mixta Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido