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

doi:10.1158/0008-5472.CAN-17-0072

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

Department of Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

55 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 language	English
Pages (from-to)	5039-5053
Number of pages	15
Journal	Cancer Research
Volume	77
Issue number	18
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-0072
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-17-0072

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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

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title = "HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells",

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.",

author = "Song, {Kwon Ho} and Choi, {Chel Hun} and Lee, {Hyo Jung} and Oh, {Se Jin} and Woo, {Seon Rang} and Hong, {Soon Oh} and Noh, {Kyung Hee} and Hanbyoul Cho and Chung, {Eun Joo} and Kim, {Jae Hoon} and Chung, {Joon Yong} and Hewitt, {Stephen M.} and Seungki Baek and Lee, {Kyung Mi} and Cassian Yee and Minjoo Son and Mao, {Chih Ping} and Wu, {T. C.} and Kim, {Tae Woo}",

note = "Funding Information: This work was funded by the National Research Foundation of Korea (NRF-2014R1A2A1A10054205 and NRF-2013M3A9D3045881). Publisher Copyright: {\textcopyright}2017 AACR.",

year = "2017",

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doi = "10.1158/0008-5472.CAN-17-0072",

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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

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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