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

Research output: Contribution to journalArticle

22 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

Fingerprint

Multiple Drug Resistance
Up-Regulation
Phenotype
Neoplasms
Epigenomics
T-Lymphocytes
Antigens
Acetylation
Cell- and Tissue-Based Therapy
Drug Resistance
Histones
Immunotherapy
Cell Cycle

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Song, K. H., Choi, C. H., Lee, H. J., Oh, S. J., Woo, S. R., Hong, S. O., ... 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
Song, Kwon Ho ; Choi, Chel Hun ; Lee, Hyo Jung ; Oh, Se Jin ; Woo, Seon Rang ; Hong, Soon Oh ; Noh, Kyung Hee ; Cho, Hanbyoul ; Chung, Eun Joo ; Kim, Jae Hoon ; Chung, Joon Yong ; Hewitt, Stephen M. ; Baek, Seungki ; Lee, Kyung Mi ; Yee, Cassian ; Son, Minjoo ; Mao, Chih Ping ; Wu, T. C. ; Kim, Tae Woo. / HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells. In: Cancer Research. 2017 ; Vol. 77, No. 18. pp. 5039-5053.
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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.",
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Song, KH, Choi, CH, Lee, HJ, Oh, SJ, Woo, SR, Hong, SO, Noh, KH, Cho, H, Chung, EJ, Kim, JH, Chung, JY, Hewitt, SM, Baek, S, Lee, KM, Yee, C, Son, M, Mao, CP, Wu, TC & Kim, TW 2017, 'HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells', Cancer Research, vol. 77, no. 18, pp. 5039-5053. https://doi.org/10.1158/0008-5472.CAN-17-0072

HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells. / Song, Kwon Ho; Choi, Chel Hun; Lee, Hyo Jung; Oh, Se Jin; Woo, Seon Rang; Hong, Soon Oh; Noh, Kyung Hee; Cho, Hanbyoul; Chung, Eun Joo; Kim, Jae Hoon; Chung, Joon Yong; Hewitt, Stephen M.; Baek, Seungki; Lee, Kyung Mi; Yee, Cassian; Son, Minjoo; Mao, Chih Ping; Wu, T. C.; Kim, Tae Woo.

In: Cancer Research, Vol. 77, No. 18, 15.09.2017, p. 5039-5053.

Research output: Contribution to journalArticle

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T1 - HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells

AU - Song, Kwon Ho

AU - Choi, Chel Hun

AU - Lee, Hyo Jung

AU - Oh, Se Jin

AU - Woo, Seon Rang

AU - Hong, Soon Oh

AU - Noh, Kyung Hee

AU - Cho, Hanbyoul

AU - Chung, Eun Joo

AU - Kim, Jae Hoon

AU - Chung, Joon Yong

AU - Hewitt, Stephen M.

AU - Baek, Seungki

AU - Lee, Kyung Mi

AU - Yee, Cassian

AU - Son, Minjoo

AU - Mao, Chih Ping

AU - Wu, T. C.

AU - Kim, Tae Woo

PY - 2017/9/15

Y1 - 2017/9/15

N2 - 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.

AB - 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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