期刊
ONCOTARGET
卷 4, 期 7, 页码 984-994出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1070
关键词
mutant p53 (mtp53); deacetylation; SIRT1; activator; triple-negative breast cancer (TNBC)
资金
- Susan G. Komen for the Cure [FAS0703858]
- National Institutes of Health [1R03CA152530]
- Nina Hyde Foundation [29XS194]
- Georgetown University Center for Drug Discovery
Many types of mutations in tumor suppressor p53 are oncogenic through gain-of-function. Therefore, targeting mutant p53 (mtp53) is a promising therapeutic approach to fight against many types of cancers. We report here a small molecule compound YK-3-237 that reduces acetylation of mtp53 and exhibits anti-proliferative effects toward triple-negative breast cancer (TNBC) cells carrying mtp53. YK-3-237 activates SIRT1 enzyme activities in vitro and deacetylation of both mtp53 and wild type p53 (WTp53) in a SIRT1-dependent manner. Deacetylation of mtp53 resulted in depletion of mtp53 protein level and up-regulated the expression of WTp53-target genes, PUMA and NOXA. YK-3-237 also induces PARP-dependent apoptotic cell death and arrests the cell cycle at G2/M phase in mtp53 TNBC cells. Taken together, our data suggest that targeting acetylation of mtp53 is a potential target to treat human cancers.
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