Integrative analysis identifies PIGK as an oncogenic glycosylphosphatidylinositol transamidase subunit with prognostic, immunological, and therapeutic relevance in head and neck cancer

Background: Glycosylphosphatidylinositol transamidase (GPI-T) catalyzes the attachment of glycosylphosphatidylinositol (GPI) anchors to membrane proteins implicated in oncogenic signaling. However, the specific contribution of individual GPI-T subunits to head and neck Cancer (HNC) remains unclear.

Methods: We first compare the expression profiles of GPI-T subunits in HNC and then integrate multi-omics analyses to assess phosphatidylinositol glycan class K (PIGK) expression, genomic alterations, function and pathway enrichment, molecular interactions, and immune associations. Clinical relevance is validated by immunohistochemistry on tissue microarray, and in vitro assays were conducted to assess PIGK-mediated phenotypes, regulation of Family with sequence similarity 20-member C (FAM20C), taxane response, and cancer-associated fibroblast (CAF) formation.

Results: Among the five subunits, PIGK was uniquely and consistently upregulated at both mRNA and protein levels in tumors. High PIGK expression correlates with aggressive clinicopathological features and poor survival across independent cohorts. Genomic analysis shows that PIGK overexpression is associated with copy number gains and inversely correlated with mutations in FAT1, CDKN2A, NOTCH1, and CASP8. Functionally, PIGK knockdown significantly suppressed cell migration, invasion, proliferation, and colony formation, reduced FAM20C expression, decreased sensitivity to paclitaxel and docetaxel, and attenuated fibroblast activation. Enrichment analysis of co-expressed genes showed involvement in cancer-related biological processes, while protein-level interactors of PIGK were enriched in GPI-anchor biosynthesis and membrane-associated pathways. Clinically, patients with PIGK ^high/FAM20C ^high profile exhibited the worst survival outcomes.

Conclusion: PIGK functions as a potential oncogenic driver in HNC with prognostic and therapeutic relevance. Its association with FAM20C, taxane response, and modulation of fibroblast activation provides insights into PIGK-mediated oncogenesis and may inform patient stratification strategies.

FAM20C; PIGK; head and neck cancer; taxane sensitivity; tumor microenvironment.