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

Cancer Res. 2017 Sep 15;77(18):5039-5053. doi: 10.1158/0008-5472.CAN-17-0072. Epub 2017 Jul 17.

Authors

Kwon-Ho Song^{1

2

3}, Chel Hun Choi^{4

5}, Hyo-Jung Lee^{1

2

3}, Se Jin Oh^{1

2

3}, Seon Rang Woo^{1

2

6}, Soon-Oh Hong^{1

2

3}, Kyung Hee Noh⁷, Hanbyoul Cho^{8

9}, Eun Joo Chung¹⁰, Jae-Hoon Kim^{8

9}, Joon-Yong Chung⁵, Stephen M Hewitt⁵, Seungki Baek^{2

3}, Kyung-Mi Lee^{2

3}, Cassian Yee^{11

12}, Minjoo Son¹³, Chih-Ping Mao¹⁴, T C Wu¹⁴, Tae Woo Kim^{15

2

3

6}

Affiliations

¹ Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Korea.
² Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
³ Department of Biomedical Science, College of Medicine, Korea University, Seoul, Korea.
⁴ Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
⁵ Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
⁶ Translational Research Institute for Incurable Diseases, Korea University College of Medicine, Seoul, Republic of Korea.
⁷ Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
⁸ Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
⁹ Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
¹⁰ Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
¹¹ Department of Melanoma Medical Oncology and Immunology, UT MDAnderson Cancer Center, Houston, Texas.
¹² Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
¹³ Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
¹⁴ Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
¹⁵ Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Korea. twkim0421@korea.ac.kr.

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. Cancer Res; 77(18); 5039-53. ©2017 AACR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Apoptosis
Biomarkers, Tumor
Breast Neoplasms / drug therapy
Breast Neoplasms / immunology
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Cell Proliferation
Combined Modality Therapy
Drug Resistance, Multiple / drug effects
Drug Resistance, Multiple / immunology*
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / immunology
Epigenesis, Genetic*
Female
Histone Deacetylase 1 / genetics
Histone Deacetylase 1 / metabolism*
Histones / metabolism
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Nanog Homeobox Protein / genetics
Nanog Homeobox Protein / metabolism*
Neoplasm Staging
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / immunology
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Prognosis
Transcriptional Activation
Tumor Cells, Cultured
Uterine Cervical Neoplasms / drug therapy
Uterine Cervical Neoplasms / immunology
Uterine Cervical Neoplasms / metabolism
Uterine Cervical Neoplasms / pathology*
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
Histones
NANOG protein, human
Nanog Homeobox Protein
HDAC1 protein, human
Histone Deacetylase 1

Grants and funding

ZIC BC011638/ImNIH/Intramural NIH HHS/United States