Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 25, Pages 15799-15811Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.641167
Keywords
estrogen receptor; G-protein-coupled receptor (GPCR); gene transcription; microRNA (miRNA); microRNA biogenesis; hormones
Categories
Funding
- National Institutes of Health [R01 CA138410]
- NIEHS, National Institutes of Health [T32 ES011564]
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Background: MicroRNA-21 (miR-21) is an oncomiR in human hepatocellular carcinoma and is highly expressed in liver, but its regulation is uncharacterized. Results: Dehydroepiandrosterone (DHEA) rapidly increases miR-21 transcription in HepG2 cells by activating G-protein-coupled estrogen receptor (GPER). Conclusion: miR-21 transcription is regulated by DHEA through GPER. Significance: GPER may be among the activators of miR-21 expression in human hepatocellular carcinoma. Little is known about the regulation of the oncomiR miR-21 in liver. Dehydroepiandrosterone (DHEA) regulates gene expression as a ligand for a G-protein-coupled receptor and as a precursor for steroids that activate nuclear receptor signaling. We report that 10 nm DHEA increases primary miR-21 (pri-miR-21) transcription and mature miR-21 expression in HepG2 cells in a biphasic manner with an initial peak at 1 h followed by a second, sustained response from 3-12 h. DHEA also increased miR-21 in primary human hepatocytes and Hep3B cells. siRNA, antibody, and inhibitor studies suggest that the rapid DHEA-mediated increase in miR-21 involves a G-protein-coupled estrogen receptor (GPER/GPR30), estrogen receptor -36 (ER36), epidermal growth factor receptor-dependent, pertussis toxin-sensitive pathway requiring activation of c-Src, ERK1/2, and PI3K. GPER antagonist G-15 attenuated DHEA- and BSA-conjugated DHEA-stimulated pri-miR-21 transcription. Like DHEA, GPER agonists G-1 and fulvestrant increased pri-miR-21 in a GPER- and ER36-dependent manner. DHEA, like G-1, increased GPER and ER36 mRNA and protein levels. DHEA increased ERK1/2 and c-Src phosphorylation in a GPER-responsive manner. DHEA increased c-Jun, but not c-Fos, protein expression after 2 h. DHEA increased androgen receptor, c-Fos, and c-Jun recruitment to the miR-21 promoter. These results suggest that physiological concentrations of DHEA activate a GPER intracellular signaling cascade that increases pri-miR-21 transcription mediated at least in part by AP-1 and androgen receptor miR-21 promoter interaction.
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