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 | |
| Publication status | Published - 2017 Sep 15 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
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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 journal › Article
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85031409431&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031409431&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-0072
DO - 10.1158/0008-5472.CAN-17-0072
M3 - Article
C2 - 28716899
AN - SCOPUS:85031409431
VL - 77
SP - 5039
EP - 5053
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 18
ER -