Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects
Myc oncoproteins and histone deacetylases (HDACs) modulate gene transcription and enhance cancer cell proliferation, and HDAC inhibitors are among the most promising new classes of anticancer drugs. Here we show that N-Myc and c-Myc up-regulated HDAC2 gene expression in neuroblastoma and pancreatic cancer cells respectively, which contributed to N-Myc- and c-Myc-induced cell proliferation. Cyclin G2 (CCNG2) was commonly repressed by N-Myc and HDAC2 in neuroblastoma cells and by c-Myc and HDAC2 in pancreatic cancer cells, and could be reactivated by HDAC inhibitors. BrdU incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for NMyc-, c-Myc and HDAC2-induced cell proliferation. Dual cross-linking chromatin immunoprecipitation assay demonstrated that N-Myc acted as a transrepressor by recruiting the HDAC2 protein to Sp1-binding sites at the CCNG2 gene core promoter. Moreover, HDAC2 was upregulated, and CCNG2 down-regulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc over-expression correlated with up-regulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of up-regulation of HDAC2 and suppression of CCNG2 in Myc-induced oncogenesis, and have significant implications for the application of HDAC inhibitors in the prevention and treatment of Mycdriven cancers.
|ISBN||1476-5594 (Electronic) 0950-9232 (Linking)|
|Authors||Marshall, G.M.; Gherardi, S.; Xu, N.; Neiron, Z.; Trahair, T.; Scarlett, C.J.; Chang, D.K.; Liu, P.K.; Jankowski, K.; Iraci, N.; Haber, M.; Norris, M.D.; Keating, J.; Sekyere, E.; Stossi, F.; Katzenellenbogen, B.S.; Biankin, A.V.; Perini, G.; Liu, T.|
|DOI||onc2010332 [pii] 10.1038/onc.2010.332|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20697349|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10629|