The Stability of Histone Acetyltransferase General Control Non-derepressible (Gcn) 5 Is Regulated by Cullin4-RING E3 Ubiquitin Ligase

摘要

Histone acetyltransferases play important roles in the regulation of chromatin structure and gene transcription. As one of the most important histone acetyltransferases, general control non-derepressible (Gcn) 5 has been linked to diverse cellular processes and tumorigenesis as well. We have recently identified a functional link between Gcn5 and acidic nucleoplasmic DNA-binding protein 1 (And-1) that is elevated in multiple cancer cells and is essential for Gcn5 protein stability. However, the mechanism by which And-1 regulates Gcn5 protein stability remains unknown. Here we show that the ablation of Cullin4-RING E3 ubiquitin ligase (CRL4) leads to the stabilization of Gcn5 in cells with depleted And-1, and Cdc10-dependent transcript 2 (Cdt2) serves as a substrate receptor protein of CRL4. Overexpression of Cdt2 reduces the Gcn5 protein levels, and CRLCdt2 is sufficient to ubiquitinate Gcn5 both in vivo and in vitro. And-1 stabilizes Gcn5 by impairing the interaction between Gcn5 and CRLCdt2 and thereby preventing Gcn5 ubiquitination and degradation. The degradation of Gcn5 is not dependent on proliferating cell nuclear antigen, an important player involved in CRLCdt2-mediated protein degradation. Thus, CRLCdt2 and And-1 play an essential role in the regulation of Gcn5 protein stability. This study provides us with the mechanistic basis to develop alternative approaches to inhibit Gcn5 activity for cancer therapy.