Sangsu Shin1, Miok Kim2,3, Seon-Jin Lee2, Kang-Seo Park4, Chang Hoon Lee5,3. 1. Department of Animal Biotechnology, Kyungpook National University, Sangju, Republic of Korea. 2. Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea. 3. Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea. 4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 5. Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea lee2014@krict.re.kr.
Abstract
BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The ability of HCC to avoid immune detection is considered one of the main factors making it difficult to cure. Abnormal histone deacetylation is thought to be one of the mechanisms for HCC immune escape, making histone deacetylases (HDACs) attractive targets for HCC treatment. Here, we investigated the effect of trichostatin A (TSA), a highly potent HDAC inhibitor, on HCC (HepG2) gene expression and function. MATERIALS AND METHODS: A genome wide-transcriptional microarray was used to identify genes regulated by TSA in HepG2 cells. Gene Ontology was used to identify pathways regulated by TSA, and these changes were confirmed by qPCR. The effect of TSA on natural killer (NK) cell-mediated killing of HCC cell lines were analyzed by both flow cytometry and LDH cytotoxicity assay. A study was also conducted in a Balb/c nude mice xenograft model to assess the anti-tumor activity of TSA. RESULTS: TSA regulated the transcription of numerous innate immunity & tumor antigen recognition-associated genes, such as ULBP1 and RAET1G, in HCC cells. In vivo, TSA reduced tumor cell growth in an NK cell-dependent manner. In vitro, TSA treatment of HepG2 cells rendered them more susceptible to NK cell-mediated killing while increasing the expression of NKGD2 ligands, including ULBP1/2/3 and MICA/B. TSA also induced direct killing of HCC cells by stimulating apoptosis. CONCLUSION: TSA likely increases killing of HCC cells indirectly by increasing NK cell-directed killing and directly by increasing apoptosis. Copyright
BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The ability of HCC to avoid immune detection is considered one of the main factors making it difficult to cure. Abnormal histone deacetylation is thought to be one of the mechanisms for HCC immune escape, making histone deacetylases (HDACs) attractive targets for HCC treatment. Here, we investigated the effect of trichostatin A (TSA), a highly potent HDAC inhibitor, on HCC (HepG2) gene expression and function. MATERIALS AND METHODS: A genome wide-transcriptional microarray was used to identify genes regulated by TSA in HepG2 cells. Gene Ontology was used to identify pathways regulated by TSA, and these changes were confirmed by qPCR. The effect of TSA on natural killer (NK) cell-mediated killing of HCC cell lines were analyzed by both flow cytometry and LDH cytotoxicity assay. A study was also conducted in a Balb/c nude mice xenograft model to assess the anti-tumor activity of TSA. RESULTS:TSA regulated the transcription of numerous innate immunity & tumor antigen recognition-associated genes, such as ULBP1 and RAET1G, in HCC cells. In vivo, TSA reduced tumor cell growth in an NK cell-dependent manner. In vitro, TSA treatment of HepG2 cells rendered them more susceptible to NK cell-mediated killing while increasing the expression of NKGD2 ligands, including ULBP1/2/3 and MICA/B. TSA also induced direct killing of HCC cells by stimulating apoptosis. CONCLUSION:TSA likely increases killing of HCC cells indirectly by increasing NK cell-directed killing and directly by increasing apoptosis. Copyright
Authors: In Hye Jung; DO Hee Kim; DA Kyung Yoo; Sun Young Baek; Seong Hoon Jeong; Dawoon E Jung; Seung Woo Park; Yong-Yoon Chung Journal: In Vivo Date: 2018 Jul-Aug Impact factor: 2.155
Authors: Melchiorre Cervello; Maria R Emma; Giuseppa Augello; Antonella Cusimano; Lydia Giannitrapani; Maurizio Soresi; Shaw M Akula; Stephen L Abrams; Linda S Steelman; Alessandro Gulino; Beatrice Belmonte; Giuseppe Montalto; James A McCubrey Journal: Aging (Albany NY) Date: 2020-02-04 Impact factor: 5.682