title: Targeting mutant p53 by a SIRT1 activator YK-3-237 inhibits the proliferation of triple-negative breast cancer cells.
abstract: 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 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 of mtp53 TNBC cells. Taken together, our data suggest that targeting acetylation of mtp53 is a potential target to treat human cancers.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Yong Weon
authors.initials: YW
authors.lastname: Yi
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Insoo
authors.initials: I
authors.lastname: Bae
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D047188:Chalcones; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000588455:YK-3-237; C447939:SIRT1 protein, human; D056564:Sirtuin 1