RESUMO
Recent research in epigenetics suggests that defects in epigenetic regulation of ribosomal DNA (rDNA) transcription may contribute to tumorigenesis. ATRX/DAXX complex is involved in the establishment and maintenance of the silence of the rDNA gene through H3K9me3 modification at histone variant H3.3. The ATRX/DAXX-related genes are frequently mutated in some types of tumors, which may increase rDNA transcription and promote cancer development and progression. In this review, we focus on the mechanism that abnormal transcription of rDNA potentially influences tumorigenesis. We also summarize the epigenetic regulatory mechanism of rDNA transcription, which may provide new theoretical support for drug development based on rDNA transcriptional regulation.
Assuntos
Carcinogênese/genética , DNA Ribossômico/genética , Epigênese Genética , Proteínas Nucleares , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Correpressoras , Histonas , Humanos , Chaperonas Moleculares , Proteínas Nucleares/genética , Proteína Nuclear Ligada ao X/genéticaRESUMO
OBJECTIVE: This study investigated the role and mechanism of action of G protein-coupled estrogen receptor (GPER) in melanogenesis. METHODS: GPER expression was detected in the A375 human melanoma cell line and B16 mouse melanoma cell line. Cell proliferation, melanin content, tyrosinase (TYR) activity, cyclic adenosine monophosphate (cAMP) level, and TYR and microphthalmia-related transcription factor (MITF) expression were measured. GPER activation was altered by agonist and antagonist treatment and its expression was downregulated by gene silencing. Estradiol-induced melanin synthesis and the activation of related signaling pathways were suppressed by inhibiting GPER via antagonist treatment. The relationship between GPER and TYR was evaluated in clinical chloasma samples by immunohistochemistry. RESULTS: Upregulation of GPER in A375 cells promoted melanogenesis, favored as indicated by increases in TYR and MITF expression and TYR activity. GPER activated melanin production via the cAMP-protein kinase (PK) A pathway, suggesting that GPER plays an important role in estrogen-induced melanin synthesis. The effect of GPER activation on cAMP-MITF-TYR signaling was also demonstrated in B16 cells. A significant association was observed between GPER and TYR expression in chloasma skin lesions relative to normal skin. CONCLUSION: GPER enhances melanin synthesis via cAMP-PKA-MITF-TYR signaling and modulates the effects of estrogen in melanogenesis. GPER is therefore a potential drug target for chloasma treatment.