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HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells

 Kwon-Ho Song  ;  Chel Hun Choi  ;  Hyo-Jung Lee  ;  Se Jin Oh  ;  Seon Rang Woo  ;  Soon-Oh Hong  ;  Kyung Hee Noh  ;  Hanbyoul Cho  ;  Eun Joo Chung  ;  Jae-Hoon Kim  ;  Joon-Yong Chung  ;  Stephen M. Hewitt  ;  Seungki Baek  ;  Kyung-Mi Lee  ;  Cassian Yee  ;  Minjoo Son  ;  Chih-Ping Mao  ;  T.C. Wu  ;  Tae Woo Kim 
 Cancer Research, Vol.77(18) : 5039-5053, 2017 
Journal Title
 Cancer Research 
Issue Date
Acetylation ; Animals ; Apoptosis ; Biomarkers, Tumor ; Breast Neoplasms/drug therapy ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology* ; Cell Proliferation ; Combined Modality Therapy ; Drug Resistance, Multiple/drug effects ; Drug Resistance, Multiple/immunology* ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/immunology ; Epigenesis, Genetic* ; Female ; Histone Deacetylase 1/genetics ; Histone Deacetylase 1/metabolism* ; Histones/metabolism ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Nanog Homeobox Protein/genetics ; Nanog Homeobox Protein/metabolism* ; Neoplasm Staging ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/immunology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology* ; Prognosis ; Transcriptional Activation ; Tumor Cells, Cultured ; Uterine Cervical Neoplasms/drug therapy ; Uterine Cervical Neoplasms/immunology ; Uterine Cervical Neoplasms/metabolism ; Uterine Cervical Neoplasms/pathology* ; Xenograft Model Antitumor Assays
Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실)
Yonsei Authors
김재훈(Kim, Jae Hoon)
조한별(Cho, Han Byoul)
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