Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis.
Histone deacetylase (HDAC) inhibitors reactivate tumor suppressor gene transcription; induce cancer cell differentiation, growth arrest, and programmed cell death; and are among the most promising new classes of anticancer drugs. Myc oncoproteins can block cell differentiation and promote cell proliferation and malignant transformation, in some cases by modulating target gene transcription. Here, we show that tissue transglutaminase (TG2) was commonly reactivated by HDAC inhibitors in neuroblastoma and breast cancer cells but not normal cells and contributed to HDAC inhibitor-induced growth arrest. TG2 was the gene most significantly repressed by N-Myc in neuroblastoma cells in a cDNA microarray analysis and was commonly repressed by N-Myc in neuroblastoma cells and c-Myc in breast cancer cells. Repression of TG2 expression by N-Myc in neuroblastoma cells was necessary for the inhibitory effect of N-Myc on neuroblastoma cell differentiation. Dual step cross-linking chromatin immunoprecipitation and protein coimmunoprecipitation assays showed that N-Myc acted as a transrepressor by recruiting the HDAC1 protein to an Sp1-binding site in the TG2 core promoter in a manner distinct from it's action as a transactivator at E-Box binding sites. HDAC inhibitor treatment blocked the N-Myc-mediated HDAC1 recruitment and TG2 repression in vitro. In neuroblastoma-bearing N-Myc transgenic mice, HDAC inhibitor treatment induced TG2 expression and demonstrated marked antitumor activity in vivo. Taken together, our data indicate the critical roles of HDAC1 and TG2 in Myc-induced oncogenesis and have significant implications for the use of HDAC inhibitor therapy in Myc-driven oncogenesis.
Liu
Tao
T
Children's Cancer Institute Australia for Medical Research and Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, High Street, Randwick, Sydney, New South Wales 2031, Australia.
Tee
Andrew E L
AE
Porro
Antonio
A
Smith
Stewart A
SA
Dwarte
Tanya
T
Liu
Pei Yan
PY
Iraci
Nunzio
N
Sekyere
Eric
E
Haber
Michelle
M
Norris
Murray D
MD
Diolaiti
Daniel
D
Della Valle
Giuliano
G
Perini
Giovanni
G
Marshall
Glenn M
GM
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D006655:Histone Deacetylases; D019204:GTP-Binding Proteins