Skin cutaneous melanoma (SKCM) continues to pose significant therapeutic challenges owing to its aggressive nature and evolving resistance mechanisms. This study investigates the under-characterized role of Hippo pathway effector TEAD4 in SKCM pathogenesis through integrated multiomics analysis of clinical cohorts (TCGA, GEO, immunotherapy cohorts) combined with functional validation in A375 cell models and xenograft systems. Our pan-cancer analysis identified TEAD4 overexpression as a strong prognostic indicator associated with poor survival and a potential association with inferior immunotherapy response. Functional experiments in A375 cells and xenograft models showed that TEAD4 knockdown impaired proliferation, migration and tumour growth while increasing necroptosis-related markers. Mechanistic investigation showed that TEAD4 directly binds the COL1A2 promoter and promotes its transcription. In A375 cells, COL1A2 overexpression attenuated TEAD4 knockdown-induced changes in AKT/mTOR signalling, necroptosis-related markers and malignant phenotypes. These findings support a TEAD4 and COL1A2 regulatory model associated with SKCM progression, AKT/mTOR pathway activity and necroptosis-related phenotypes, and suggest TEAD4 as a prognostic factor and potential biomarker associated with immunotherapy outcome that requires further validation.
Keywords: AKT/mTOR; COL1A2; TEAD4; necroptosis; skin cutaneous melanoma.
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