C-terminus of Hsc70-interacting protein regulates C-terminal binding protein 2 and the expression of its target genes

C-terminal binding protein 2 (CtBP2) is a transcriptional co-repressor involved in cell migration, apoptosis, and tumorization. Up-regulation of CtBP2 is implicated in various human cancers including breast cancers. In our present study, we found that the C-terminus of Hsc70-interacting protein (CHIP) regulated the steady-state level of CtBP2. CHIP interacted with CtBP2 via a tetratricopeptide domain in the nucleus and ubiquitinated CtBP2, marking it for proteasomal degradation. Depletion of CHIP resulted in stabilization of the CtBP2 protein, which was not affected by ultraviolet irradiation. Finally, CHIP expression regulated the expression of CtBP2 target genes. Taken together, our data demonstrate that CHIP regulates the steady-state level of CtBP2 as an E3 ubiquitin ligase and determines the expression levels of CtBP2 target genes. Regulating CtBP2 levels with CHIP may be a useful therapeutic strategy in human cancers.

► The CtBP2 protein level is inversely correlated with CHIP expression.
► CHIP interacts with CtBP2 via TPR domain in the nucleus.
► CHIP ubiquitinates CtBP2 for proteasomal degradation as an E3 ubiquitin ligase.
► CHIP expression regulates the expression of CtBP2 target genes.
► Regulating CtBP2 with CHIP may be a useful therapeutic strategy in human cancers.