Nificance: HDAC3 regulates cell cycle progression by controlling cyclin A levels. PCAF and GCN5 acetylate cyclin A at precise lysine residues targeting it for degradation at mitosis. We report right here that histone deacetylase 3 (HDAC3) straight interacts with and deacetylates cyclin A. HDAC3 interacts using a domain included within the first 171 aa of cyclin A, a area involved within the regulation of its stability. In cells, overexpression of HDAC3 reduced cyclin A acetylation whereas the knocking down of HDAC3 improved its acetylation. Furthermore, reduction of HDAC3 levels induced a decrease of cyclin A that can be reversed by proteasome inhibitors. These outcomes indicate that HDAC3 is able to regulate cyclin A degradation throughout mitosis by means of proteasome. Interestingly, HDAC3 is abruptly degraded at mitosis also via proteasome as a result facilitating cyclin A acetylation by PCAF/GCN5, that will target cyclin A for degradation. Since cyclin A is crucial for S phase progression and mitosis entry, the knock down of HDAC3 affects cell cycle progression especially at both, S phase and G2/M transition. In summary we propose here that HDAC3 regulates cyclin A stability by counteracting the action in the acetylases PCAF/GCN5.Cyclin A will be the regulatory subunit of quite a few members from the cyclindependent kinase family members (cdks)2 that play a vital role throughout cell cycle progression. Especially, cyclin A associates with and activates cdk2 as a result driving S phase progression. Moreover, in addition, it binds to and activates cdk1, a kinase vital for G2/M transition (1). The part of cyclin Acdk complexes during cell cycle would be to phosphorylate a plethora of substrates that consist of a significant quantity of transcription elements as for example Sp1, NFY, FOXK2, and PR (2), transcriptional repressors as pRb and RBP1 (six), or proteins involved in epige This work was supported by Grants SAF200907769 in the Ministerio deCiencia e Innovaci of Spain and Reticc RD06/0020/0010 in the Istituto de Salud Carlos III.2413767-30-1 Order 1 To whom correspondence must be addressed: Department of Cell Biology, Immunology, and Neurosciences, Institut d’Investigacions Biom iques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain. Tel.: 934035286; Fax: 934021907; E-mail: obachs@ ub.edu. 2 The abbreviations used are: cdk, cyclindependent kinase; APC/C, anaphasepromoting complex/cyclosome; HDAC, histone deacetylase; OA, okadaic acid.3-Amino-2,2-difluoropropanoic acid Chemscene netic gene silencing as EZH2 (7).PMID:27108903 As a result cyclin Acdk complexes play a critical function inside the regulation of gene expression throughout cell cycle progression. Cyclin A levels are low through G1 but they improve in the onset of S phase, when it contributes towards the stimulation of DNA synthesis (8, 9). Its levels stay elevated till early mitosis when, by associating with and activating cdk1, it drives the initiation of chromosome condensation and nuclear envelope breakdown (ten 2). Another cyclin, cyclin B, also activates cdk1 at mitosis. Cyclin B levels rise in the course of G2, after which it binds to cdk1. This complex promotes the completion of chromosome condensation and spindle assembly, therefore driving cell cycle progression until metaphase (13). To proceed with metaphase to anaphase transition, the inactivation of each cyclin Acdk1 and cyclin Bcdk1 complexes is needed. Their inactivation is achieved by degradation of each cyclins. Cyclin A is destroyed during prometaphase by the Anaphase Advertising Complex/Cyclosome (APC/C) through proteasome (14) whereas cyclin B is d.