title: Histone deacetylase inhibitors suppress mutant p53 transcription via HDAC8/YY1 signals in triple negative breast cancer cells.
abstract: There is an urgent need to investigate the potential targeted therapy approach for triple-negative breast cancer (TNBC). Our present study reveals that histone deacetylase inhibitors (HDACIs) suberoyl anilide hydroxamic acid (SAHA) and sodium butyrate (NaB) significantly inhibit cell proliferation, arrest cell cycle at G0/G1 phase, and induce mitochondrial related apoptosis of TNBC cells. Further, SAHA and NaB decrease the phosphorylation, protein and mRNA levels of mutant p53 (mtp53) in TNBC cells. While SAHA or NaB has no similar inhibition effect on wild type p53 (wtp53). The inhibition apparently occurs at the level of transcription because the down regulation of precursor p53 transcription is much more rapid (less than 2h) and sharp than that of mature p53. The knockdown of HDAC8, while not HDAC6, inhibits the transcription of mtp53 in TNBC cells. The luciferase assay and ChIP analysis reveal that both SAHA and NaB can reduce the binding of transcription factor Yin Yang 1 (YY1) with the -102 to -96 position of human p53 promoter. Knockdown of YY1 also significantly inhibits the transcription of mtp53 in TNBC cells. Further, SAHA and NaB can inhibit the association of HDAC8 and YY1, increase acetylation of residues 170-200 of YY1, then decrease its transcription activities, and finally suppress YY1 induced p53 transcription. Together, our data establish that SAHA and NaB can be considered as drug candidates for TNBC patients, and HDAC8/YY1/mtp53 signals act as an important target for TNBC treatment.
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Department of Medical Genetics & Cell Biology, School of Basic Sciences, Guangzhou Medical University, Guangzhou 511436, China.
authors.forename: Zhao-Tong
authors.initials: ZT
authors.lastname: Wang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: chenzhj@sysucc.org.cn.
authors.forename: Zhuo-Jia
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
authors.forename: Guan-Min
authors.initials: GM
authors.lastname: Jiang
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ying-Min
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Histology and Embryology, Guangdong Medical College, Zhanjiang 524023, China.
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Yi
authors.affiliation: Department of Medical Genetics & Cell Biology, School of Basic Sciences, Guangzhou Medical University, Guangzhou 511436, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: whongsh@mail.sysu.edu.cn.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
mesh_terms: D017209:Apoptosis; D020148:Butyric Acid / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000077337:Vorinostat; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D020148:Butyric Acid; D000077337:Vorinostat; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: Histone deacetylase inhibitors; Mtp53; TNBC; Transcription; YY1