title: Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability.
abstract: The histone deacetylases (HDACs), Sirtuin 1 (Sirt1) and Sirt2, play crucial roles in many biological processes, including cell proliferation, differentiation and apoptosis. HDAC inhibitors have been considered as a potential therapeutic approach for various types of cancers. Here, we demonstrated that the Sirt1 and Sirt2 inhibitors EX527 and AGK2 suppressed cell growth and caused G1 phase arrest by inhibiting the expression of Cdk6 and/or Cdk4. An agar colony formation assay revealed that EX527 and AGK2 decreased colony formation in soft agar. Furthermore, EX527 and AGK2 pretreatment inhibited the expression of HSF1 and HSP27 and induced HSF1 ubiquitination. Sirt1 overexpression increased HSF1 expression and/or stabilization and induced cell migration in a scratch assay. Overall, these results indicate that EX527 and AGK2 suppress cell growth and migration by inhibiting HSF1 protein stability.
authors.affiliation: Department of Pathology, School of Dentistry, Chosun University, Gwangju 501-759, Republic of Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dongguk University, Gyeongju 780-714, Republic of Korea.
authors.forename: Soo-A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Pathology, School of Dentistry, Chosun University, Gwangju 501-759, Republic of Korea.
authors.forename: Sang-Gun
authors.initials: SG
authors.lastname: Ahn
mesh_terms: D002227:Carbazoles / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005663:Furans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D055550:Protein Stability / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; C521855:AGK2 compound; D002227:Carbazoles; D004268:DNA-Binding Proteins; D005663:Furans; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D011804:Quinolines; D014157:Transcription Factors; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2