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

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26 Citations (Scopus)

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 languageEnglish
Pages (from-to)5039-5053
Number of pages15
JournalCancer Research
Volume77
Issue number18
DOIs
Publication statusPublished - 2017 Sep 15

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Song, K. H., Choi, C. H., Lee, H. J., Oh, S. J., Woo, S. R., Hong, S. O., Noh, K. H., Cho, H., Chung, E. J., Kim, J. H., Chung, J. Y., Hewitt, S. M., Baek, S., Lee, K-M., Yee, C., Son, M., Mao, C. P., Wu, T. C., & Kim, T. W. (2017). HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells. Cancer Research, 77(18), 5039-5053. https://doi.org/10.1158/0008-5472.CAN-17-0072