Histone deacetylase inhibitors promote ATP2A3 gene expression in hepatocellular carcinoma cells: p300 as a transcriptional regulator
Por:
Hernandez-Oliverasa, Andres, Izquierdo-Torres, Eduardo, Meneses-Morales, Ivan, Rodriguez, Gabriela, Zarain-Herzberg, Angel, Santiago-Garcia, Juan
Publicada:
1 ene 2019
Resumen:
Sarco(endo)plasmic reticulum Ca2+-ATPases (SERCA)expression is reduced or absent in several types of cancer and cancer cell lines; however, their expression and regulation in hepatocellular carcinoma (HCC)are unknown. Histone deacetylase inhibitors (HDACi)increase SERCA3 mRNA expression in gastric and breast cancer cell lines by increasing H3K9ac and binding of Sp1 and Sp3 transcription factors to the promoter; however, the molecular mechanism is not fully understood. Our results show that ATP2A3 (SERCA3)gene expression is decreased in human HCC samples and rat HCC AS-30D cells compared to normal liver, and HCC patients with high expression of ATP2A3 had longer overall survival than those with low expression. Sodium butyrate (NaB)and trichostatin A (TSA)increase SERCA3 mRNA expression in AS-30D cells, whereas SERCA2b mRNA expression did not change. NaB and TSA increase H3K9ac and H3K27ac in two ATP2A3 promoter regions. Besides, NaB treated cells increased Sp1 and Sp3 occupancy at ATP2A3 promoter; whereas TSA treated cells showed increased p300 levels at ATP2A3 promoter. Inhibition of p300 by C646, a specific inhibitor, mitigates SERCA3 mRNA induction by TSA, and reduces more than 70% of basal SERCA3 mRNA expression, suggesting that p300 is important for ATP2A3 gene transcription in AS-30D cells. Moreover, inhibition of p300 decreases H3K9ac in TSA treated cells. Our results provide evidence of decreased SERCA3 expression in human HCC samples and rat AS-30D cells and a correlation of SERCA3 expression with overall survival in HCC patients. Also, reveal new insights in SERCA3 transcriptional regulation mediated by HDACi. © 2019 Elsevier Ltd
Filiaciones:
Hernandez-Oliverasa, Andres:
Programa de Doctorado en Ciencias de la Salud, Universidad Veracruzana, Veracruz, Mexico
Instituto de Investigaciones Biológicas, Universidad Veracruzana, Xalapa, Veracruz, Mexico
Univ Veracruzana, Programa Doctorado Ciencias Salud, Xalapa, Veracruz, Mexico
Univ Veracruzana, Inst Invest Biol, Luis Castelazo Ayala S-N, Xalapa 91190, Veracruz, Mexico
Izquierdo-Torres, Eduardo:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City, DF, Mexico
Meneses-Morales, Ivan:
Facultad de Ciencias Químicas de la Universidad Juárez del Estado de Durango, Mexico
Univ Judrez Estado Durango, Fac Ciencias Quim, Durango, Dgo, Mexico
Rodriguez, Gabriela:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City, DF, Mexico
Zarain-Herzberg, Angel:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City, DF, Mexico
Santiago-Garcia, Juan:
Instituto de Investigaciones Biológicas, Universidad Veracruzana, Xalapa, Veracruz, Mexico
Univ Veracruzana, Inst Invest Biol, Luis Castelazo Ayala S-N, Xalapa 91190, Veracruz, Mexico
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