title: Epigenetic suppression of the antitumor cytotoxicity of NK cells by histone deacetylase inhibitor valproic acid.
abstract: Natural killer (NK) cells play an essential role in the fight against tumor development. The therapeutic use of autologous NK cells has been exploited to treat human malignancies, yet only limited antitumor activity is observed in cancer patients. In this study, we sought to augment the antitumor activity of NK cells using epigenetic approaches. Four small molecules that have been known to promote epigenetic reprogramming were tested for their ability to enhance the activity of NK cells. Using a tumor cell lysis assay, we found that the DNA demethylating agent 5-azacytidine and vitamin C did not significantly affect the tumor killing ability of NK cells. The thyroid hormone triiodothyronine (T3) slightly increased the activity of NK cells. The histone deacetylase inhibitor valproic acid (VPA), however, inhibited NK cell lytic activity against leukemic cells in a dose-dependent manner. Pretreatment using VPA reduced IFNγ secretion, impaired CD107a degranulation, and induced apoptosis by activating the PD-1/PD-L1 pathway. VPA downregulated the expression of the activating receptor NKG2D (natural-killer group 2, member D) by inducing histone K9 hypermethylation and DNA methylation in the gene promoter. Histone deacetylase inhibitors have been developed as anticancer agents for use as monotherapies or in combination with other anticancer therapies. Our data suggest that the activity of histone deacetylase inhibitors on NK cell activity should be considered in drug development.
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Meizi
authors.initials: M
authors.lastname: Cui
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Niu
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Jianting
authors.initials: J
authors.lastname: Xu
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgical Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing 100021, China.
authors.forename: Yushun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: BASO Cell Science & Technology Co., Ltd Zhuhai, Guangdong 519015, China.
authors.forename: Weisheng
authors.initials: W
authors.lastname: Kong
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Jiuwei
authors.initials: J
authors.lastname: Cui
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin UniversityChangchun, Jilin 130021, China; Stanford University Medical School, Palo Alto Veterans Institute for ResearchPalo Alto, CA 94304, USA.
authors.forename: Jifan
authors.initials: J
authors.lastname: Hu
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University Changchun, Jilin 130021, China.
authors.forename: Haofan
authors.initials: H
authors.lastname: Jin
keywords: DNA methylation; NK cell; apoptosis; epigenetics; expression; histone methylation; tumor killing; valproic acid