DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells

Directed by microarray analyses, we report that autocrine human growth hormone (hGH) increased the mRNA and protein expression of DNA methyltransferase 1 (DNMT1), DNMT3A and DNMT3B in mammary carcinoma cells. Autocrine hGH stimulation of DNMT3A and DNMT3B expression was mediated by JAK2 and Src kinases, and treatment of mammary carcinoma cells with the DNMT inhibitor, 5'-aza-2'-deoxycytidine (AZA), abrogated autocrine hGH-stimulated cellular proliferation, apoptosis and anchorage-independent growth. AZA reversed the epitheliomesenchymal transition of mammary carcinoma cells induced by autocrine hGH, to an epithelioid morphology and abrogated cell migration stimulated by autocrine hGH. Autocrine hGH-stimulated hypermethylation of the first exon of the PLAKOGLOBIN gene and AZA abrogated the ability of autocrine hGH to repress plakoglobin gene transcription. Small interfering RNA (siRNA)-mediated depletion of the individual DNMT molecules did not release autocrine hGH repression of PLAKOGLOBIN promoter activity nor did individual DNMT depletion affect autocrine hGH-stimulated migration. However, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B abrogated hypermethylation of the PLAKOGLOBIN gene stimulated by autocrine hGH and subsequent repression of plakoglobin gene transcription and increased cell migration. Thus, the autocrine hGH-stimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent phenotypic conversion of mammary carcinoma cells. Autocrine hGH, therefore, utilizes DNA methylation as a mechanism to exert its oncogenic effects in mammary carcinoma cells.

pharmacology, breast neoplasms, gene expression regulation, rna, dna, small interfering, report, development, neoplasm proteins, dna (cytosine-5-)-methyltransferase, neoplasm, activity, genetics, drug effects, gene, biosynthesis, growth, autocrine communication, apoptosis, human growth hormone, humans, gamma catenin, proteins, antineoplastic, phenotype, cell line, neoplastic, analogs & derivatives, metabolism, antagonists & inhibitors, antimetabolites, messenger, research, female, cell movement, pathology, growth hormone, cell proliferation, human, expression, dna methylation, tumor, protein, promoter regions (genetics), growth-hormone, cytidine monophosphate

10.1038/sj.onc.1210917

0950-9232

2602-2612

Shafiei, F.

73e4a731-2c05-4405-974b-153299dbc57b

Rahnama, F.

6aa2cd11-7391-4405-bd18-02caae6ee444

Pawella, L.

c83729eb-0b05-4cd9-b32e-5455cd54f0ad

Mitchell, M.D.

91c6cdd2-93ce-4ff8-b0d2-9de84c3b14fa

Gluckman, P.D.

492295c0-ef71-4871-ad5a-771c98e1059a

Lobie, P.E.

d1d009de-75f1-4460-8478-e46b6104515f

2008

Shafiei, F.

73e4a731-2c05-4405-974b-153299dbc57b

Rahnama, F.

6aa2cd11-7391-4405-bd18-02caae6ee444

Pawella, L.

c83729eb-0b05-4cd9-b32e-5455cd54f0ad

Mitchell, M.D.

91c6cdd2-93ce-4ff8-b0d2-9de84c3b14fa

Gluckman, P.D.

492295c0-ef71-4871-ad5a-771c98e1059a

Lobie, P.E.

d1d009de-75f1-4460-8478-e46b6104515f

Shafiei, F., Rahnama, F., Pawella, L., Mitchell, M.D., Gluckman, P.D. and Lobie, P.E. (2008) DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells. Oncogene, 27 (18), 2602-2612. (doi:10.1038/sj.onc.1210917).

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Published date: 2008

Keywords: pharmacology, breast neoplasms, gene expression regulation, rna, dna, small interfering, report, development, neoplasm proteins, dna (cytosine-5-)-methyltransferase, neoplasm, activity, genetics, drug effects, gene, biosynthesis, growth, autocrine communication, apoptosis, human growth hormone, humans, gamma catenin, proteins, antineoplastic, phenotype, cell line, neoplastic, analogs & derivatives, metabolism, antagonists & inhibitors, antimetabolites, messenger, research, female, cell movement, pathology, growth hormone, cell proliferation, human, expression, dna methylation, tumor, protein, promoter regions (genetics), growth-hormone, cytidine monophosphate