Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors.
Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with histone deacetylase inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, histone deacetylase inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, histone deacetylase inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53.
Blagosklonny
Mikhail V
MV
New York Medical College, Valhalla, New York 12208, USA. blagosklonny@hotmail.com
Trostel
Shana
S
Kayastha
Ganesh
G
Demidenko
Zoya N
ZN
Vassilev
Lyubomir T
LT
Romanova
Larisa Y
LY
Bates
Susan
S
Fojo
Tito
T
D000107:Acetylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D004317:Doxorubicin; C087123:romidepsin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2