Regulation of thyroid hormone receptor and c-erbA mRNA levels by butyrate in neuroblastoma (N2A) and glioma (C6) cells.
Butyrate produced a biphasic modulation of the thyroid hormone receptor in neuroblastoma N2A cells increasing receptor number by 20-35% at concentrations 0.25-0.75 mM and decreasing receptor levels by 30-55% at 2-4 mM. The half-life of the receptor, as assessed by its disappearance after incubation with 18 microM cycloheximide was 8.4 hr in control cells and 10.3 hr and 5.0 hr in cells incubated with 0.25 and 4 mM butyrate, respectively. This compound increased the abundance of multyacetylated forms of histone H4 from 30% in control cells to almost 70% with butyrate 4 mM. In glioma C6 cells, the fatty acid produced a dose-dependent increase of receptor levels (up to 3-4-fold with 2-5 mM butyrate) and had little effect in increasing multiacetylation (from 30% in controls to 42-46% with 2-5 mM butyrate). Recent studies have shown that the c-erbA proto-oncogen codes for the thyroid hormone receptor. In N2A and C6 cells, 2 c-erbA-related mRNAs, one measuring 2.6 kb and the other 6 kb, were detected. Both forms were differently regulated by butyrate. This compound decreased the abundance of the 2.6 kb forms in both cell types, even at the concentrations at which there was an elevation of receptor levels. Only the largest mRNA correlated with receptor concentration increasing by 2-3-fold after treatment of C6 cells with butyrate, and undergoing a smaller but biphasic change in N2A cells. Our data suggest that modification of chromatin structure probably secondary to acetylation induces changes in thyroid hormone receptor levels in neuroblastoma and glioma cells by affecting both receptor stability and receptor mRNA levels.
Yusta
B
B
Instituto de Investigaciones Biomedicas, Consejo Superior de Investigaciones Cientificas, Madrid.
Ortiz-Caro
J
J
Bedo
G
G
Pascual
A
A
Aranda
A
A
D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002455:Cell Division; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000473:pathology*; D006207:Half-Life; D006657:Histones / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology*; D011061:Poly A / Q000096:biosynthesis*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis*; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D002087:Butyrates; D006657:Histones; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011988:Receptors, Thyroid Hormone; D020148:Butyric Acid; D011061:Poly A