Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis
Protein S-palmitoylation, a dynamic and reversible post-translational modification involving the attachment of palmitate to cysteine residues, is a key regulator of protein functionality and cellular signaling. Dysregulation of this modification has emerged as a critical driver of cancer progression, influencing oncogenes and signaling pathways. Among the 23 DHHC palmitoyl transferases responsible for catalyzing S-palmitoylation, aberrant expression of specific members is linked to tumorigenesis and development, underscoring their potential as promising therapeutic targets. However, the cancer-specific roles and substrates of individual DHHC enzymes remain poorly characterized. In this study, we identified DHHC9 as a crucial regulator of adenocarcinoma progression, including colorectal and lung cancers. Functional studies demonstrated that DHHC9 knockdown profoundly inhibited cell migration in vitro and tumor metastasis in vivo. Proteomic analysis revealed STRN4, a core component of the STRIPAK complex, as a DHHC9-specific substrate whose palmitoylation promotes YAP nuclear localization and activates Hippo pathway effectors CCN1, CCN2, and ANKRD1, driving cancer cell migration. Notably, we discovered two small molecules, treprostinil and 10-HCPT, as potent DHHC9 inhibitors that effectively suppressed adenocarcinoma cell migration. Our findings illuminate a pivotal role for DHHC9 in adenocarcinoma metastasis and unveil its potential as a highly promising therapeutic target in cancer treatment, opening new avenues for intervention in palmitoylation-driven malignancies.