title: Suberoylanilide hydroxamic acid (SAHA) inhibits EGF-induced cell transformation via reduction of cyclin D1 mRNA stability.
abstract: Suberoylanilide hydroxamic acid (SAHA) inhibiting cancer cell growth has been associated with its downregulation of cyclin D1 protein expression at transcription level or translation level. Here, we have demonstrated that SAHA inhibited EGF-induced Cl41 cell transformation via the decrease of cyclin D1 mRNA stability and induction of G0/G1 growth arrest. We found that SAHA treatment resulted in the dramatic inhibition of EGF-induced cell transformation, cyclin D1 protein expression and induction of G0/G1 growth arrest. Further studies showed that SAHA downregulation of cyclin D1 was only observed with endogenous cyclin D1, but not with reconstitutionally expressed cyclin D1 in the same cells, excluding the possibility of SAHA regulating cyclin D1 at level of protein degradation. Moreover, SAHA inhibited EGF-induced cyclin d1 mRNA level, whereas it did not show any inhibitory effect on cyclin D1 promoter-driven luciferase reporter activity under the same experimental conditions, suggesting that SAHA may decrease cyclin D1 mRNA stability. This notion was supported by the results that treatment of cells with SAHA decreased the half-life of cyclin D1 mRNA from 6.95 h to 2.57 h. Consistent with downregulation of cyclin D1 mRNA stability, SAHA treatment also attenuated HuR expression, which has been well-characterized as a positive regulator of cyclin D1 mRNA stability. Thus, our study identifies a novel mechanism responsible for SAHA inhibiting cell transformation via decreasing cyclin D1 mRNA stability and induction of G0/G1 growth arrest in Cl41 cells.
authors: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Rd, Haidian District, Beijing 100191, China.
authors: Jingjie
authors: J
authors: Zhang
authors: Weiming
authors: W
authors: Ouyang
authors: Jingxia
authors: J
authors: Li
authors: Dongyun
authors: D
authors: Zhang
authors: Yonghui
authors: Y
authors: Yu
authors: York
authors: Y
authors: Wang
authors: Xuejun
authors: X
authors: Li
authors: Chuanshu
authors: C
authors: Huang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051959:ELAV Proteins / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006207:Half-Life; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D020871:RNA Stability; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013997:Time Factors; D000077337:Vorinostat
chemical_list: D051959:ELAV Proteins; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D019938:Cyclin D1; D000077337:Vorinostat; D004815:Epidermal Growth Factor