Cleavage and Cytoplasmic Relocalization of Histone Deacetylase 3 Are Important for Apoptosis Progression

Abstract

The apoptotic process is accompanied by major changes in chromatin structure and gene expression. The apoptotic genetic program is progressively set up with the inhibition of antiapoptotic genes and the activation of proapoptotic ones. Here, we show that the histone deacetylase 3 (HDAC-3), which is a known corepressor of many proapoptotic genes, is subjected to proteolytic cleavage during apoptosis in a cell type- and species-independent manner. This cleavage is caspase dependent and leads to the loss of the C-terminal part of HDAC-3. The cleaved form of HDAC-3 accumulates in the cytoplasm. Furthermore, we found that forced nuclear localization of HDAC-3 decreases the efficiency of apoptosis induction, indicating that HDAC-3 cytoplasmic relocalization is important for the apoptotic process. Finally, we observed that HDAC-3 cleavage allowed increased histone acetylation and transcriptional activation on a proapoptotic HDAC-3-target gene, the Fas-encoding gene. Altogether, our results thus indicate that HDAC-3 cleavage is crucial for efficient apoptosis induction because it allows the activation of some proapoptotic genes during apoptosis progression.

SUPPLEMENTAL MATERIAL

We thank V. Régnier for help with DT40 culture; K. Helin and S. Müller for materials; L. Baricault for materials and helpful discussions; and C. Carron, T. Levade, and members of the D. Trouche's lab for helpful discussions.

This work was supported by a grant from the “Fondation de France” to D.T. F.E. was supported by fellowships from the “Ligue Nationale Contre le Cancer” and the “Fondation de France.” O.V. was a recipient of a studentship from the “Ligue Nationale Contre le Cancer.”