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.