ZEB1 and ALKBH5 coregulate CRABP2 and FABP5 and jointly determine the sensitivity of anaplastic thyroid cancers to gemcitabine and retinoic acid.

Retinoic acid (RA) signaling through CRABP2 and FABP5 differentially influences therapeutic responses and drug resistance in anaplastic thyroid cancer (ATC), yet regulatory mechanisms remain unclear. Our study reveals low CRABP2 and high FABP5 expression in ATC cell lines (THJ-11T/16T/21T), with RA alone showing no growth inhibition but RA/gemcitabine (GEM) combination exhibiting synergistic effects. ZEB1 transcriptionally regulates both proteins, where RA/GEM treatment alters its promoter binding pattern-reducing FABP5 association while enhancing CRABP2 binding. Co-regulators KAT2B and EP300 compete for ZEB1's CP domain during transcriptional regulation. Notably, RA/GEM modulates m(6)A modifications: suppressing CRABP2 and enhancing FABP5 methylation through METTL3/ALKBH5 interactions, thereby reducing mRNA stability. Clinical analysis of 286 thyroid cancer specimens confirmed variable CRABP2/FABP5 expression. Crucially, ZEB1 and ALKBH5 overexpression potentiated GEM/RA efficacy against ATCs. These findings identify m(6)A-mediated post-transcriptional regulation and ZEB1-driven transcriptional dynamics as key determinants of the combined effects of GEM and RA in ATCs, providing new targets for combination therapy optimization.