Geminin Mediates FoxO3 Deacetylation By HDAC3

Geminin,a ploypeptide of about 25 kDa,is a multifunctional protein and occurs in nuclei.Geminin plays a fundamental role in the regulation of embryonic development,cell cycle,the maintenance of chromosomal integrity and tumorigenesis.Geminin negatively regulates Cdtl function to ensure DNA must be replicated once and only once during each cell cycle.Geminin also involves in embryonic development as an inhibitory or induction factor at different developmental stages.It can regulate the development of the eye and the embryo by interaction with the homologous box protein Six3 and Hox.HDAC3 is a member of Rpd3/Hadl deacetylase family,which regulates the deacetylation of histone lysine residues,HDAC3 only through the interaction with other proteins to form a multi-subunit complex to activation deacetylase activity,and then interacts with other proteins to mediate a specific site of gene transcription.However,little is known how HDAC3 specifies its substrates for modulation among those highly homologous transcription factor family members.Here we report that Geminin is a new binding partner of Fox03.Brest cancer cells depleted of Geminin results in Fox03 acetylation;HDAC3 deficiency also facilitates Fox03 acetylation.However,depletion of Geminin and HDAC3 does not result in Fox03 further acetylation.It is suggested that HDAC3-Geminin axis regulates Fox03 deacetylation.In addition,HDAC3 direct binds to Geminin and HDAC3 does not direct bind to Fox03,but Geminin,HDAC3 and Fox03 are a complex,which is co-localization in nuclei.Our results demonstrate that Geminin is a substrate-specifying factor to couple HDAC3 and Fox03,thereby specifically facilitating Fox03 deacetylation.