title: Enhancing the anticancer effect of the histone deacetylase inhibitor by activating transglutaminase.
abstract: Histone deacetylase (HDAC) inhibitors have shown promising anticancer effects in clinical trials. However, a proportion of patients do not respond to HDAC inhibitor therapy. We have previously demonstrated that tissue transglutaminase (TG2) is one of the genes commonly up-regulated by HDAC inhibitors in vitro and in vivo, and that two structurally distinct TG2 protein isoforms, the full-length (TG2-L) and the short form (TG2-S), exert opposing effects on cell differentiation due to difference in transamidation activity. Here we show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) transcriptionally activates the expression of both TG2-L and TG2-S, and that up-regulation of TG2-L renders neuroblastoma cells less sensitive to SAHA-induced cytotoxicity. Combination therapy with SAHA and the transamidation activator Naringenin, a natural product found in citrus fruits, synergistically enhanced transamidation activity and SAHA-induced cytotoxicity in neuroblastoma cells, but not in normal non-malignant cells. In tumour-bearing N-Myc transgenic mice, SAHA and Naringenin synergistically suppressed tumour progression. Taken together, our data demonstrate that SAHA-induced TG2-L over-expression renders cancer cells less sensitive to SAHA therapy, and suggest the addition of Naringenin to SAHA and probably also other HDAC inhibitors in future clinical trials in cancer patients.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Dora
authors.initials: D
authors.lastname: Ling
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.forename: Pei Y
authors.initials: PY
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Nelson
authors.forename: Siiri E
authors.initials: SE
authors.lastname: Iismaa
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D044950:Flavanones / Q000494:pharmacology; D019204:GTP-Binding Proteins; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000032:analysis; D011503:Transglutaminases / Q000235:genetics / Q000502:physiology*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D044950:Flavanones; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D000077337:Vorinostat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; C005273:naringenin