Endogenous reactivation of the RARbeta2 tumor suppressor gene epigenetically silenced in breast cancer.
Loss of expression of retinoic acid receptor beta2 (RARbeta2), a potent tumor suppressor gene, is commonly observed during breast carcinogenesis. RARbeta2 silencing can be traced to epigenetic chromatin changes affecting the RARbeta P2 promoter. Here we show that retinoic acid therapy fails to induce RARbeta2 in primary breast tumors, which carry a methylated RARbeta P2 promoter. DNA methylation leads to repressive chromatin deacetylation at RARbeta P2. By inducing an appropriate level of histone reacetylation at RARbeta P2 we could reactivate endogenous RARbeta2 transcription from unmethylated as well as methylated RARbeta P2 in breast cancer cell lines and xenograft tumors, and obtain significant growth inhibition both in vitro and in vivo. This study may have translational implications for breast cancer and other cancers carrying an epigenetically silenced RARbeta P2 promoter.
Sirchia
Silvia M
SM
Laboratory of Genetics and Biochemistry, San Paolo University Hospital, School of Medicine, University of Milan, 20142 Milan, Italy.
Ren
Mingqiang
M
Pili
Roberto
R
Sironi
Elena
E
Somenzi
Giulia
G
Ghidoni
Riccardo
R
Toma
Salvatore
S
Nicolò
Guido
G
Sacchi
Nicoletta
N
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006657:Histones; D006877:Hydroxamic Acids; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; C012589:trichostatin A; D014212:Tretinoin