Abstract
Purpose: It is well known that methylation plays an important role in regulating tissue expression of proopiomelanocortin (POMC) and recent studies have shown that demethylation can occur also in vitro in neuroendocrine tumors. Aim of the present study was to evaluate whether inhibition of methylation modulates POMC expression and ACTH secretion by human corticotrope tumors. Methods: Twenty two ACTH-secreting pituitary tumors were incubated with 5-AZA-2′-deoxycytidine (AZA), an inhibitor of DNA-methyltransferases, with or without 10 nM corticotropin-releasing hormone (CRH). Both dose response (100 nM–10 μM AZA) and time course (4–96 h) experiments were carried out for measurement of ACTH secretion and POMC gene expression. Results: Incubation with AZA increased constitutive POMC expression and ACTH secretion by human corticotrope adenomas. The effect appeared most notable at 24 and 48 h with 1 μM AZA. Incubation with AZA did not exert an additional stimulatory effect on CRH-stimulated POMC and ACTH. Conclusions: The present study shows that AZA increases POMC gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. This can be taken to indicate that mechanisms set into motion by AZA play a role in the regulation of ACTH secretion/POMC expression in tumoral corticotropes and paves the way to further studies in Cushing’s disease.
| Original language | English |
|---|---|
| Pages (from-to) | 464-469 |
| Number of pages | 6 |
| Journal | Pituitary |
| Volume | 17 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Oct 1 2014 |
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Keywords
- 5-AZA-2′-deoxycytidine
- ACTH
- Corticotrope adenoma
- Cushing’s disease
- Methylation
- POMC
ASJC Scopus subject areas
- Endocrinology
- Endocrinology, Diabetes and Metabolism
- Medicine(all)
Cite this
AZA-Deoxycytidine stimulates proopiomelanocortin gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. / Cassarino, Maria Francesca; Sesta, Antonella; Pagliardini, Luca; Losa, Marco; Lasio, Giovanni; Cavagnini, Francesco; Pecori Giraldi, Francesca.
In: Pituitary, Vol. 17, No. 5, 01.10.2014, p. 464-469.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - AZA-Deoxycytidine stimulates proopiomelanocortin gene expression and ACTH secretion in human pituitary ACTH-secreting tumors
AU - Cassarino, Maria Francesca
AU - Sesta, Antonella
AU - Pagliardini, Luca
AU - Losa, Marco
AU - Lasio, Giovanni
AU - Cavagnini, Francesco
AU - Pecori Giraldi, Francesca
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Purpose: It is well known that methylation plays an important role in regulating tissue expression of proopiomelanocortin (POMC) and recent studies have shown that demethylation can occur also in vitro in neuroendocrine tumors. Aim of the present study was to evaluate whether inhibition of methylation modulates POMC expression and ACTH secretion by human corticotrope tumors. Methods: Twenty two ACTH-secreting pituitary tumors were incubated with 5-AZA-2′-deoxycytidine (AZA), an inhibitor of DNA-methyltransferases, with or without 10 nM corticotropin-releasing hormone (CRH). Both dose response (100 nM–10 μM AZA) and time course (4–96 h) experiments were carried out for measurement of ACTH secretion and POMC gene expression. Results: Incubation with AZA increased constitutive POMC expression and ACTH secretion by human corticotrope adenomas. The effect appeared most notable at 24 and 48 h with 1 μM AZA. Incubation with AZA did not exert an additional stimulatory effect on CRH-stimulated POMC and ACTH. Conclusions: The present study shows that AZA increases POMC gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. This can be taken to indicate that mechanisms set into motion by AZA play a role in the regulation of ACTH secretion/POMC expression in tumoral corticotropes and paves the way to further studies in Cushing’s disease.
AB - Purpose: It is well known that methylation plays an important role in regulating tissue expression of proopiomelanocortin (POMC) and recent studies have shown that demethylation can occur also in vitro in neuroendocrine tumors. Aim of the present study was to evaluate whether inhibition of methylation modulates POMC expression and ACTH secretion by human corticotrope tumors. Methods: Twenty two ACTH-secreting pituitary tumors were incubated with 5-AZA-2′-deoxycytidine (AZA), an inhibitor of DNA-methyltransferases, with or without 10 nM corticotropin-releasing hormone (CRH). Both dose response (100 nM–10 μM AZA) and time course (4–96 h) experiments were carried out for measurement of ACTH secretion and POMC gene expression. Results: Incubation with AZA increased constitutive POMC expression and ACTH secretion by human corticotrope adenomas. The effect appeared most notable at 24 and 48 h with 1 μM AZA. Incubation with AZA did not exert an additional stimulatory effect on CRH-stimulated POMC and ACTH. Conclusions: The present study shows that AZA increases POMC gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. This can be taken to indicate that mechanisms set into motion by AZA play a role in the regulation of ACTH secretion/POMC expression in tumoral corticotropes and paves the way to further studies in Cushing’s disease.
KW - 5-AZA-2′-deoxycytidine
KW - ACTH
KW - Corticotrope adenoma
KW - Cushing’s disease
KW - Methylation
KW - POMC
UR - http://www.scopus.com/inward/record.url?scp=84952321299&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84952321299&partnerID=8YFLogxK
U2 - 10.1007/s11102-013-0527-8
DO - 10.1007/s11102-013-0527-8
M3 - Article
VL - 17
SP - 464
EP - 469
JO - Pituitary
JF - Pituitary
SN - 1386-341X
IS - 5
ER -