Histone deacetylase inhibitors (HDACi) are an emerging cancer therapy; however, their effect on natural killer (NK) cell-mediated anti-tumor responses remain unknown. Here, we evaluated the impact of a benzamide HDACi, entinostat, on human primary NK cells as well as tumor cell lines. Entinostat significantly upregulated the expression of NKG2D, an essential NK cell activating receptor. Independently, entinostat augmented the expression of ULBP1, HLA, and MICA/B on both rhabdomyosarcoma and Ewing sarcoma cell lines. Additionally, entinostat increased both cytotoxicity and IFN-γ production in human NK cells following coculture with these tumor cells. Mechanistically, entinostat treatment resulted in increased chromatin accessibility to the promoter region for interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) gene and thereby increasing the transcript and protein levels of IFIT1 that augmented the IFIT1-mediated IRF1, STAT4, and STING pathways. Corresponding transcriptome analysis revealed enrichment of IRF1 and STAT4 and gene sets responsible for NK cell-mediated IFN-γ production and cytotoxicity, respectively. Our results show a novel mechanism by which entinostat initiates an IFIT1-STINGmediated potentiation of STAT4 via IRF1 to augment NK cell-mediated anti-tumor responses.

Background: The World Economic Forum (2011) concluded that the economic impact of mental illness is the single most important contributor among all non-communicable diseases to loss of productivity. The 21 economies represented by Asia Pacific Economic Cooperation (APEC) responded to that information with efforts to address mental health as an integral component of economic development. Aim: In order to help assess the progress of APEC region compared to other regions of the world, the World Health Organization (WHO) granted us access to a subset of the 2014 Mental Health Atlas database containing health indicators from all 21 APEC economies. Methods: APEC-specific data were extracted using the same format used by WHO in its Mental Health Atlas to compare/contrast data in APEC versus the six WHO regions of the world. Results: It was observed that mental health workforces in APEC include a higher number of psychiatrist providers compared with WHO regions. Suicide rates reported in three APEC economies are among the highest in the world. All APEC economies continue their individual and coordinated efforts to support their ‘ APEC Roadmap to Promote Mental Wellness in a Healthy Asia Pacific (2014–2020)’. Conclusion: Significant challenges for APEC members exist to coordinate regional efforts to improve mental health due to highly variable income levels, existing health infrastructures and social preferences. The findings in this report may serve as a helpful baseline for measuring success within the APEC region by 2020, the year in which progress in support of economic development will be reassessed.