Histone deacetylase inhibitors promote the expression of ATP2A3 gene in breast cancer cell lines.
Recent studies have shown that expression of Sarco(endo)plasmic Reticulum Ca(2+) -ATPase 2 (SERCA2) is decreased in oral cancer; whereas expression of SERCA3 is considerably decreased or absent in human colon, gastric, breast, and lung cancers. The ATP2A2 and ATP2A3 genes encode SERCA2 and SERCA3 isoforms, respectively. Promoter methylation on CpG islands was responsible for the repression of ATP2A2 gene in human oral cancer samples. On the other hand, histone deacetylase inhibitors (HDACi) up-regulate ATP2A3 expression in gastric, colon, and lung cancer cells in culture, however, the molecular mechanism is unknown. In this study, we investigate whether HDACi and DNA methylation regulate ATP2A2 and ATP2A3 expression in human breast cancer cell lines. Results show a marked induction of SERCA3a and pan-SERCA3 mRNA expression in human MCF-7 and MDA-MB-231 cells treated with sodium butyrate (NaB) or trichostatin A (TSA); whereas SERCA2b mRNA expression did not change significantly. ChIP assays show that NaB or TSA treatment of MDA-MB-231 cells increases H3K9 acetylation on ATP2A3 promoter. NaB also decreases H3K9 trimethylation; suggesting that these modifications stimulate ATP2A3 gene expression, through a chromatin remodeling mechanism. In contrast, NaB or TSA do not increase H3K9-acetylation of ATP2A2 proximal promoter. In addition, treatment with 5-aza-2'-deoxycytidine did not affect SERCA2b and SERCA3a expression, suggesting that promoter methylation status does not alter their expression in these cell lines. We propose that alteration of SERCA2b/SERCA3a isoform expression ratio could affect calcium management within the cell, and thus, the cellular pathways regulated by calcium could be compromised, such as cellular proliferation or apoptosis. © 2015 Wiley Periodicals, Inc.
Programa de Doctorado en Ciencias Biomédicas, Universidad Veracruzana, Veracruz, México.|Instituto de Investigaciones Biol, ó, gicas, Universidad Veracruzana, Xalapa, Veracruz, México.
Erika
E
Contreras-Leal
Instituto de Investigaciones Biol, ó, gicas, Universidad Veracruzana, Xalapa, Veracruz, México.
Andrés
A
Hernández-Oliveras
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México.
Lucía
L
Flores-Peredo
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México.
Ángel
Á
Zarain-Herzberg
Instituto de Investigaciones Biol, ó, gicas, Universidad Veracruzana, Xalapa, Veracruz, México. jusantiago@uv.mx.
Juan
J
Santiago-García
D001943:Breast Neoplasms / Q000235:genetics*; D020148:Butyric Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D015854:Up-Regulation
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020148:Butyric Acid; C012589:trichostatin A; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; C506949:ATP2A3 protein, human
ChIP assay; DNA methylation; HDAC inhibitors; SERCA mRNA expression; breast cancer cells