Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling

Abstract

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.

Histone demethylase KDM2A: Biological functions and clinical values (Review)

“…In addition, there are also significant functional differences between the subtypes (17). For example, the alternative isoform of KDM2A lacking the N-terminal demethylase domain can negatively regulate canonical Wnt signaling (12,(17)(18)(19)(20).…”

Podocyte lineage marker expression is preserved across Wilms tumor subtypes and enhanced in tumors harboring the SIX1/2 p.Q177R mutation

“…Positive regulators of non-canonical WNT/PCP signaling include non-canonical WNT ligand WNT5A (Qian et al 2007, Nishita et al 2010), IQGAP2 through interaction with Cdc42/Rac1 (Logue et al 2011, Ozdemir et al 2018, Fukata et al 2002), ARHGEF3 through activation of RhoA (D’Amato et al 2015, You et al 2021), and FOXC1 through direct regulation of WNT5A expression (Han et al 2018). Negative regulators of canonical WNT/β-catenin signaling include WNT5A through interaction with the receptor Ror2 (Mikels and Nusse 2006), KDM2B through independent demethylation of β-catenin and transcriptional repression of β-catenin target genes (Lu et al 2015, Ladinovich et al 2020), as well as SLIT3 and IQGAP2 as the expression of both has been associated with decreased β-catenin target gene activation or decreased nuclear β-catenin, respectively (Kim et al 2018, Ng et al 2018, Deng et al 2016). These findings suggest imbalance in WNT/β-catenin signaling in favor of non-canonical WNT/PCP may contribute to the enhanced aggressive nature of SIX1/2miRNA tumors.…”

Conserved Genes in Highly Regenerative Metazoans Are Associated with Planarian Regeneration

“…Based on previous research into head regeneration in planaria, it can be inferred that HRJDa could be related to maintenance of anterior body segments in planaria ( Gurley et al 2008 ; Tian et al 2021 ; Wang et al 2021 ). Also, demethylases have been implicated in numerous studies to modulate Wnt signaling pathways ( Jiang et al 2013 ; Lu et al 2015 ; Lađinović et al 2020 ). This could indicate a relationship with developmental and wound response processes, regulated via Wnt signaling pathways.…”