Abstract
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 upregulated 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. 5-bromo-2′- deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc-and HDAC2-induced cell proliferation. Dual crosslinking 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 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation 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 Myc-driven cancers.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5957-5968 |
| Number of pages | 12 |
| Journal | Oncogene |
| Volume | 29 |
| Issue number | 44 |
| DOIs | |
| State | Published - Nov 4 2010 |
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Keywords
- N-Myc
- c-Myc
- cell proliferation
- cyclin G2
- histone deacetylase 2
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
Cite this
Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects. / Marshall, G. M.; Gherardi, S.; Xu, N.; Neiron, Z.; Trahair, T.; Scarlett, C. J.; Chang, D. K.; Liu, P. Y.; Jankowski, K.; Iraci, N.; Haber, M.; Norris, M. D.; Keating, J.; Sekyere, E.; Jonquieres, G.; Stossi, F.; Katzenellenbogen, Benita S; Biankin, A. V.; Perini, G.; Liu, T.
In: Oncogene, Vol. 29, No. 44, 04.11.2010, p. 5957-5968.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects
AU - Marshall, G. M.
AU - Gherardi, S.
AU - Xu, N.
AU - Neiron, Z.
AU - Trahair, T.
AU - Scarlett, C. J.
AU - Chang, D. K.
AU - Liu, P. Y.
AU - Jankowski, K.
AU - Iraci, N.
AU - Haber, M.
AU - Norris, M. D.
AU - Keating, J.
AU - Sekyere, E.
AU - Jonquieres, G.
AU - Stossi, F.
AU - Katzenellenbogen, Benita S
AU - Biankin, A. V.
AU - Perini, G.
AU - Liu, T.
PY - 2010/11/4
Y1 - 2010/11/4
N2 - 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 upregulated 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. 5-bromo-2′- deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc-and HDAC2-induced cell proliferation. Dual crosslinking 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 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation 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 Myc-driven cancers.
AB - 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 upregulated 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. 5-bromo-2′- deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc-and HDAC2-induced cell proliferation. Dual crosslinking 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 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation 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 Myc-driven cancers.
KW - N-Myc
KW - c-Myc
KW - cell proliferation
KW - cyclin G2
KW - histone deacetylase 2
UR - http://www.scopus.com/inward/record.url?scp=78149468828&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78149468828&partnerID=8YFLogxK
U2 - 10.1038/onc.2010.332
DO - 10.1038/onc.2010.332
M3 - Article
C2 - 20697349
AN - SCOPUS:78149468828
VL - 29
SP - 5957
EP - 5968
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 44
ER -