Specific activity of class II histone deacetylases in human breast cancer cells.
Although numerous studies have underlined the role of histone deacetylases (HDAC) in breast physiology and tumorigenesis, little is known on the particular contribution of the various classes of HDACs in these processes. Using estrogen receptor-alpha (ERalpha)-positive MCF-7 breast cancer cells, the effects of MC1575 and MC1568, two novel class II-specific HDAC inhibitors, were analyzed on cell proliferation, apoptosis, and estrogen signaling. The specificity of these HDAC inhibitors was validated by measuring histone and alpha-tubulin acetylation and by the specific in vitro inhibition of recombinant HDAC4 using histone and nonhistone substrates, contrasting with the lack of inhibition of class I HDACs. In addition, MC1575 did not inhibit class I HDAC gene expression, thus confirming the specific targeting of class II enzymes. Similar to trichostatin A (TSA), MC1575 displayed a dose-dependent antiproliferative effect and induced cell cycle arrest although this blockade occurred at a different level than TSA. Moreover, and in contrast to TSA, MC1575 had no effect on MCF-7 cells apoptosis. Interestingly, MC1575 was able to increase p21(waf1/CIP1) mRNA levels but did not regulate the expression of other genes such as cyclin D1, p27, p14(ARF), Bcl2, Baxalpha, Trail-R1, and Trail-R2. Finally, MC1575 strongly induced ERbeta gene expression but did not decrease ERalpha expression, nor did it switch hydroxytamoxifen to an agonist activity. Altogether, these data suggest that the class II HDAC subfamily may exert specific roles in breast cancer progression and estrogen dependence.
Duong
Vanessa
V
Institut de Recherche en Cancérologie de Montpellier, INSERM U896, Parc Euromédecine, Montpellier, France.
Bret
Caroline
C
Altucci
Lucia
L
Mai
Antonello
A
Duraffourd
Céline
C
Loubersac
Julie
J
Harmand
Pierre-Olivier
PO
Bonnet
Sandrine
S
Valente
Sergio
S
Maudelonde
Thierry
T
Cavailles
Vincent
V
Boulle
Nathalie
N
D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D047628:Estrogen Receptor alpha; D006877:Hydroxamic Acids; C583610:MC1575; D011758:Pyrroles; D012097:Repressor Proteins; C447828:HDAC10 protein, human; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; C433811:HDAC6 protein, human; C543273:HDAC7 protein, human; C486544:HDAC9 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases