Abstract
Transcriptional silencing via promoter methylation of genes important for cell growth and differentiation plays a key role in myeloid leukemogenesis. We find that clinically achievable levels of 5-aza-2′-deoxycytidine (5-AZA-dC), a potent inhibitor of DNA methylation, can modify chromatin and restore the ability of tumor necrosis factor α (TNFα) to induce monocytic differentiation of the acute myeloid leukemia cells NB4 and U937. Although 5-AZA-dC cannot fully induce differentiation, we show that 5-AZA-dC acts directly on TNFα-responsive promoters to facilitate TNFα-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFα target gene, by deacetylating chromatin domains in a methylation-dependent manner. Chromatin immunoprecipitation analyses of the Dif-2 promoter show histone hyperacetylation and a recruitment of the nuclear factor-κB transcription factor in response to 5-AZA-dC. Furthermore, 5-AZA-dC plus TNFα enhances the level of phosphorylated RNAP ol II at the Dif-2 promoter via synergistic recruitment of TFIIH. We conclude that nonspecific changes in chromatin can allow a specific transcriptional inducer to overcome blocks in leukemic cell differentiation. Our results support the concept of low doses of 5-AZA-dC acting in combination with other agents to target epigenetic changes that drive malignant growth in leukemic cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 55-64 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 69 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2009 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Inhibition of DNA methyltransferase activates tumor necrosis factor α-induced monocytic differentiation in acute myeloid leukemia cells. / Laurenzana, Anna; Petruccelli, Luca A.; Pettersson, Filippa; Figueroa, Maria; Melnick, Ari; Baldwin, Albert S.; Paoletti, Francesco; Miller, Wilson H.
In: Cancer Research, Vol. 69, No. 1, 01.01.2009, p. 55-64.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of DNA methyltransferase activates tumor necrosis factor α-induced monocytic differentiation in acute myeloid leukemia cells
AU - Laurenzana, Anna
AU - Petruccelli, Luca A.
AU - Pettersson, Filippa
AU - Figueroa, Maria
AU - Melnick, Ari
AU - Baldwin, Albert S.
AU - Paoletti, Francesco
AU - Miller, Wilson H.
PY - 2009/1/1
Y1 - 2009/1/1
N2 - Transcriptional silencing via promoter methylation of genes important for cell growth and differentiation plays a key role in myeloid leukemogenesis. We find that clinically achievable levels of 5-aza-2′-deoxycytidine (5-AZA-dC), a potent inhibitor of DNA methylation, can modify chromatin and restore the ability of tumor necrosis factor α (TNFα) to induce monocytic differentiation of the acute myeloid leukemia cells NB4 and U937. Although 5-AZA-dC cannot fully induce differentiation, we show that 5-AZA-dC acts directly on TNFα-responsive promoters to facilitate TNFα-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFα target gene, by deacetylating chromatin domains in a methylation-dependent manner. Chromatin immunoprecipitation analyses of the Dif-2 promoter show histone hyperacetylation and a recruitment of the nuclear factor-κB transcription factor in response to 5-AZA-dC. Furthermore, 5-AZA-dC plus TNFα enhances the level of phosphorylated RNAP ol II at the Dif-2 promoter via synergistic recruitment of TFIIH. We conclude that nonspecific changes in chromatin can allow a specific transcriptional inducer to overcome blocks in leukemic cell differentiation. Our results support the concept of low doses of 5-AZA-dC acting in combination with other agents to target epigenetic changes that drive malignant growth in leukemic cells.
AB - Transcriptional silencing via promoter methylation of genes important for cell growth and differentiation plays a key role in myeloid leukemogenesis. We find that clinically achievable levels of 5-aza-2′-deoxycytidine (5-AZA-dC), a potent inhibitor of DNA methylation, can modify chromatin and restore the ability of tumor necrosis factor α (TNFα) to induce monocytic differentiation of the acute myeloid leukemia cells NB4 and U937. Although 5-AZA-dC cannot fully induce differentiation, we show that 5-AZA-dC acts directly on TNFα-responsive promoters to facilitate TNFα-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFα target gene, by deacetylating chromatin domains in a methylation-dependent manner. Chromatin immunoprecipitation analyses of the Dif-2 promoter show histone hyperacetylation and a recruitment of the nuclear factor-κB transcription factor in response to 5-AZA-dC. Furthermore, 5-AZA-dC plus TNFα enhances the level of phosphorylated RNAP ol II at the Dif-2 promoter via synergistic recruitment of TFIIH. We conclude that nonspecific changes in chromatin can allow a specific transcriptional inducer to overcome blocks in leukemic cell differentiation. Our results support the concept of low doses of 5-AZA-dC acting in combination with other agents to target epigenetic changes that drive malignant growth in leukemic cells.
UR - http://www.scopus.com/inward/record.url?scp=58249110388&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58249110388&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-0245
DO - 10.1158/0008-5472.CAN-08-0245
M3 - Article
VL - 69
SP - 55
EP - 64
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 1
ER -