Targeting Mutant p53 by a SIRT1 Activator YK-3-237 Inhibits the Proliferation of Triple-Negative Breast Cancer Cells
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Yong Weon Yi1,*, Hyo Jin Kang1,*, Hee Jeong Kim1, Yali Kong3, Milton L. Brown3 and Insoo Bae1,2,3
1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
2 Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
3 Center for Drug Discovery, Georgetown University, Washington, DC
* These authors contributed equally
Milton L. Brown, email:
Insoo Bae, email:
Keywords: mutant p53 (mtp53), deacetylation, SIRT1, activator, triple-negative breast cancer (TNBC)
Received: May 31, 2013 Accepted: June 20, 2013 Published: July 5, 2013
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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