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¹ Department of Pathology, Haartman Institute, University of Helsinki, FIN-00014 Helsinki
² Department of Virology, Haartman Institute, University of Helsinki, FIN-00014 Helsinki
³ Department of Pediatrics, Kuopio University Hospital and University of Kuopio, FIN-70211 Kuopio, Finland

(Requests for offprints should be addressed to J Liu; Email: Jiangi.Liu{at}helsinki.fi)

Aberrant DNA methylation may be involved in human adrenocortical tumorigenesis, which is often accompanied by abnormal hormone production. In this study, we aimed to clarify the effects of DNA methylation on steroidogenesis using the human adrenocortical NCI-H295R cell line as a model. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (Azad; 10 µM for 7 days) decreased the proliferation rate to approximately 20% and the cell number to 60% of the control, with a simultaneous increase in the expression of the cyclin-dependent kinase inhibitor p57^KIP2 gene. In addition, Azad treatment increased cortisol secretion dose and time dependently, whereas dehydroepiandrosterone sulfate secretion was not affected. Azad treatment decreased basal and (Bu)₂cAMP-induced expression of low- and high-density lipoprotein receptor, steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme, steroid 17-hydroxylase/17,20-lyase and steroid 21-hydroxylase mRNA, as well as the StAR protein level. In contrast, Azad treatment increased the basal expression of steroid 11ß-hydroxylase and 3ß-hydroxysteroid dehydrogenase/⁵-⁴-isomerase genes, although it inhibited the (Bu)₂cAMP-induced expression of these two genes. The expression of steroidogenic factor-1 (SF-1) and DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X-chromosome 1) genes (both harboring putative CpG islands in their promoters) and the methylation degree of the HpaII recognition site(s) in the SF-1 gene promoter region were reduced by Azad treatment. The immunostaining pattern of the methyl-CpG-binding protein MeCP2 was also modified by Azad treatment. These results suggest that DNA methylation may be implicated in the regulation of cell proliferation and steroidogenesis in human adrenocortical cells.

This article has been cited by other articles:

				P. Utriainen, J. Liu, T. Kuulasmaa, and R. Voutilainen Inhibition of DNA methylation increases follistatin expression and secretion in the human adrenocortical cell line NCI-H295R J. Endocrinol., February 1, 2006; 188(2): 305 - 310. [Abstract] [Full Text] [PDF]