WSTF-associated regulation of GLYCTK and metabolic adaptation in colorectal cancer

Background Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide, driven by complex genetic and epigenetic factors. The Williams syndrome transcription factor (WSTF/BAZ1B), an emerging oncogenic factor, has been implicated in chromatin remodeling and genome stability. However, the precise mechanisms in CRC progression, particularly the metabolic reprogramming processes, remain unclear. Methods This study integrated transcriptomic, metabolomic, genome-wide ChIP-seq and summary-data-based Mendelian randomization (SMR) analyses in CRC cells and patient cohorts to study the WSTF regulatory network. WSTF knockdown and overexpression cell lines were combined with RNA-seq, LC-MS metabolomics and ChIP-seq annotation to identify direct targets and affected pathways. Multi-omics SMR using CRC GWAS, eQTL and mQTL datasets, together with bulk and single-cell RNA-seq, immune infiltration, functional assays and molecular docking were applied to explore GLYCTK as a candidate downstream effector of WSTF and a putative CRC-associated marker. Results WSTF knockdown reprogrammed transcription and metabolism, activating glucose and stress-response pathways while suppressing ribosome biogenesis, genetic information processing and MYC-related programs. ChIP-seq suggested that WSTF mainly binds to promoter-proximal, GC-rich motifs and identified GLYCTK as a candidate downstream target whose expression is inversely associated with WSTF. SMR analysis suggested a methylation-dependent regulatory relationship in which GLYCTK expression is associated with CRC risk. The immune infiltration analyses suggested that GLYCTK is associated with an immune-cold tumor microenvironment, whereas functional assays indicated that GLYCTK promotes proliferation, migration and invasion in CRC cells. Drug screening identified phenylbiguanide and hydroxyfasudil as candidate compounds targeting GLYCTK-associated networks. Conclusions WSTF may contribute to CRC progression through transcriptional and epigenetic-associated regulation of metabolic adaptation, while GLYCTK may represent a context-dependent downstream factor associated with CRC susceptibility and development.