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