Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner

Abstract

Canonical Wnt signaling is essential for a plethora of biological processes ranging from early embryogenesis to aging. Malfunctions of this crucial signaling pathway are associated with various developmental defects and diseases, including cancer. Although TCF/LEF transcription factors (TCF/LEFs) are known to be essential for this pathway, the regulation of their intracellular levels is not completely understood. Here, we show that the lysine demethylase KDM2A promotes the proteasomal destabilization of TCF/LEFs independently of its demethylase domain. We found that the KDM2A-mediated destabilization of TCF/LEFs is dependent on the KDM2A zinc finger CXXC domain. Furthermore, we identified the C-terminal region of TCF7L2 and the CXXC domain of KDM2A as the domains responsible for the interaction between the two proteins. Our study is also the first to show that endogenous TCF/LEF proteins undergo KDM2A-mediated proteasomal degradation in a neddylation-dependent manner. Here, we reveal a completely new mechanism that affects canonical Wnt signaling by regulating the levels of TCF/LEF transcription factors through their KDM2A-promoted proteasomal degradation.

Interplay between Wnt signaling molecules and exosomal miRNAs in breast cancer (Review)

“…Wnt signaling leads to elevated levels of β-catenin in the nucleus, which binds to TCF/LEF and promotes alterations in transcriptional mechanisms, resulting in the activation of several target genes. In addition, KDM2A promotes the degradation of TCF/LEF transcription factors, which regulate canonical Wnt signaling ( 50 ). The transfer of proteins from the E-cadherin-binding pool to the cytoplasmic pool increases the amount of free β-catenin available to activate target genes.…”