Crosstalk between Fat Mass and Obesity-related (FTO) and multiple WNT signaling pathways

Abstract

Fat Mass and Obesity-related (FTO) gene is associated with a diverse set of human diseases. Yet, the functional landscape of FTO remains largely unknown, most likely owing to its wide range of mechanistic roles and cell-type-specific targets. Here, we discover the intricate role of FTO in multiple WNT signaling pathways. Re-analyses of public data identified the bifurcation of canonical and noncanonical WNT pathways as the major role of FTO. In FTO-depleted cells, we find that the canonical WNT/{beta}-Catenin signaling is inhibited in a non-cell autonomous manner via the upregulation of DKK1. Simultaneously, this upregulation of DKK1 promotes cell migration via activating the noncanonical WNT/PCP pathway. Unexpectedly, we also find that the canonical WNT/STOP signaling induces the accumulation of cytoplasmic FTO proteins. This subsequently leads to the stabilization of mRNAs via RNA demethylation, revealing a previously uncharacterized mode of WNT action in RNA regulation. Altogether, this study places the functional context of FTO at the branching point of multiple WNT signaling pathways which may explain the wide spectrum of FTO functions.