Oestrogen receptor alpha increases p21(WAF1/CIP1) gene expression and the antiproliferative activity of histone deacetylase inhibitors in human breast cancer cells.
We analysed the antiproliferative activity of various histone deacetylase (HDAC) inhibitors such as trichostatin A (TSA) on human breast cancer cells. We observed a lower sensitivity to HDAC inhibition for oestrogen receptor negative (ER-) versus positive (ER+) cell lines. This differential response was associated neither with a modification of drug efflux via the multidrug resistance system nor with a global modification of histone acetyltransferase (HAT)/HDAC activities. In contrast, we demonstrated that in ER+ breast cancer cells the p21(WAF1/CIP1) gene was more sensitive to TSA regulation and was expressed at higher levels. These differences were observed both in transient transfection experiments and on the endogenous p21(WAF1/CIP1) gene. The Sp1 transcription factor, which was shown to interact in vitro with both class I and class II HDACs, is sufficient to confer the differential sensitivity to TSA and participated in the control of p21(WAF1/CIP1) basal expression. Finally, re-expression of ERalpha following adenoviral infection of ER- breast cancer cells increased both p21(WAF1/CIP1) protein accumulation and the growth inhibitory activity of TSA. Altogether, our results highlight the key role of ERalpha and p21(WAF1/CIP1) gene expression in the sensitivity of breast cancer cells to hyperacetylating agents.
Margueron
R
R
INSERM U540, Endocrinologie Moléculaire et Cellulaire des Cancers and Université de Montpellier I, 60, rue de Navacelles, 34090 Montpellier, France.
Licznar
A
A
Lazennec
G
G
Vignon
F
F
Cavaillès
V
V
D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D016329:Sp1 Transcription Factor; C012589:trichostatin A