The Multifaceted Tumor Suppressor SASH1: From Molecular Scaffold to Clinical Biomarker and Therapeutic Target

Abstract

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor scaffold protein frequently downregulated in diverse cancers. Its loss, driven by epigenetic silencing, microRNAs, and altered protein interactions, promotes proliferation, epithelial–mesenchymal transition (EMT), invasion, and therapy resistance. Mechanistically, SASH1 integrates major oncogenic pathways, including PI3K/Akt/mTOR, TGF-β, Hippo/ YAP, and CRKL/SRC signaling, while maintaining cell adhesion and cytoskeletal integrity. Clinically, reduced SASH1 expression is involved in advanced tumor stage, metastasis, and poor prognosis. Restoration of SASH1 expression, including pharmacological induction such as with chloropyramine, has shown anti-tumor effects in preclinical models and partial restoration of chemosensitivity, although evidence remains experimental. Overall, SASH1 represents a promising prognostic biomarker and potential therapeutic target that warrants further translational investigation.