Abstract
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.
Original language | English |
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Pages (from-to) | 5039-5053 |
Number of pages | 15 |
Journal | Cancer Research |
Volume | 77 |
Issue number | 18 |
DOIs | |
Publication status | Published - 2017 Sep 15 |
Bibliographical note
Funding Information:This work was funded by the National Research Foundation of Korea (NRF-2014R1A2A1A10054205 and NRF-2013M3A9D3045881).
Publisher Copyright:
©2017 AACR.
All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research