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.

• Keywords
• KDM2A, TCF/LEF, canonical Wnt signaling, neddylation, ubiquitination,
• MeSH
• beta Catenin * metabolism   MeSH
• Lysine * MeSH
• Wnt Signaling Pathway MeSH
• Zinc Fingers MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• beta Catenin * MeSH
• Lysine * MeSH

A precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they still have the ability to bind to CpG islands in promoters and to interact with their protein partners via their other functional domains. We have observed that KDM2A-SF and KDM2B-SF bind to the promoters of axin 2 and cyclin D1, two canonical Wnt signaling target genes, and repress their activity. Moreover, KDM2A-SF and KDM2B-SF are both able to strongly repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to negatively affect the transcription of canonical Wnt signaling target genes by binding to their promoters and by interacting with TCF7L1 and other co-repressors.

• MeSH
• CpG Islands MeSH
• Cyclin D1 genetics   metabolism   MeSH
• Jumonji Domain-Containing Histone Demethylases genetics   metabolism   MeSH
• F-Box Proteins genetics   metabolism   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Lysine genetics   metabolism   MeSH
• Promoter Regions, Genetic * MeSH
• Protein Isoforms MeSH
• Transcription Factor 7-Like 1 Protein genetics   metabolism   MeSH
• Gene Expression Regulation * MeSH
• Wnt Signaling Pathway * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CCND1 protein, human MeSH Browser
• Cyclin D1 MeSH
• Jumonji Domain-Containing Histone Demethylases MeSH
• F-Box Proteins MeSH
• KDM2A protein, human MeSH Browser
• Lysine MeSH
• Protein Isoforms MeSH
• Transcription Factor 7-Like 1 Protein MeSH
• TCF7L1 protein, human MeSH Browser

Aberrant levels of histone modifications lead to chromatin malfunctioning and consequently to various developmental defects and human diseases. Therefore, the proteins bearing the ability to modify histones have been extensively studied and the molecular mechanisms of their action are now fairly well understood. However, little attention has been paid to naturally occurring alternative isoforms of chromatin modifying proteins and to their biological roles. In this review, we focus on mammalian KDM2A and KDM2B, the only two lysine demethylases whose genes have been described to produce also an alternative isoform lacking the N-terminal demethylase domain. These short KDM2A/B-SF isoforms arise through alternative promoter usage and seem to play important roles in development and disease. We hypothesise about the biological significance of these alternative isoforms, which might represent a more common evolutionarily conserved regulatory mechanism.

• Keywords
• KDM2A; KDM2B; lysine demethylase; epigenetics; chromatin; alternative isoform; alternative promoter,
• MeSH
• Jumonji Domain-Containing Histone Demethylases deficiency   genetics   metabolism   MeSH
• Isoenzymes deficiency   genetics   metabolism   MeSH
• Humans MeSH
• Neoplasms enzymology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Jumonji Domain-Containing Histone Demethylases MeSH
• Isoenzymes MeSH