The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation.
Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) beta(2) is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARbeta2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARbeta2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARbeta2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (betaRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARbeta2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.
Raif
Anna
A
Children's Cancer Institute Australia for Medical Research, Randwick, NSW 2031, Australia.
Marshall
Glenn M
GM
Bell
Jessica L
JL
Koach
Jessica
J
Tan
Owen
O
D'andreti
Carla
C
Thomas
Wayne
W
Sekyere
Eric
E
Norris
Murray
M
Haber
Michelle
M
Kavallaris
Maria
M
Cheung
Belamy B
BB
D000107:Acetylation; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D019938:Cyclin D1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D014157:Transcription Factors / Q000502:physiology*; D014212:Tretinoin / Q000627:therapeutic use*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D018168:Receptors, Retinoic Acid; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C082925:retinoic acid receptor beta; D019938:Cyclin D1; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; C117731:TRIM16 protein, human; D044767:Ubiquitin-Protein Ligases