Role of Yes-associated protein and transcriptional coactivator with PDZ-binding motif in the malignant transformation of oral submucous fibrosis

•Matrix stiffness is a necessary step for the perpetuation of fibrosis and malignancy.•Yes-associated protein as mechanical transducers promote the migratory phenotype.•Matrix stiffness mediate malignant transformation by the senescence escape pathway.•Reprogramming of stiff matrix restore fibrosis-associated tumor development.•Restoration of the Hippo pathway reverses fibrosis-associated malignancy. The objective of the present manuscript is to elucidate the role of matrix stiffness in the malignant transformation of oral submucous fibrosis. The role of matrix stiffness in several cancers including oral cancer was reviewed with a tailored search strategy using relevant keywords as per the Medline format. The role of molecular mediators, Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) was weighed in the context of OSF along two distinct pathways. Increased matrix stiffness activates the transcriptional coactivators, YAP and TAZ shuttling between the nucleus and cytoplasm. YAP and TAZ, serve as mechanical transducers in promoting cell migration, invasion and epithelial-mesenchymal transition (EMT). The hypoxic microenvironment in the advanced stage of OSF promotes the migratory phenotype through mechanical memory. Reprogramming of a stiff matrix has the potential to restore the Hippo-YAP/TAZ tumor suppressor pathway and reverse fibrosis-associated tumor development.