Recapitulating the potential contribution of protein S-palmitoylation in cancer.

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Protein S-palmitoylation is a reversible form of protein lipidation in which the formation of a thioester bond occurs between a cysteine (Cys) residue of a protein and a 16-carbon fatty acid chain. This modification is catalyzed by a family of palmitoyl acyl transferases, the DHHC enzymes, so called because of their Asp-His-His-Cys (DHHC) catalytic motif. Deregulation of DHHC enzymes has been linked to various diseases, including cancer and infections. Cancer, a major cause of global mortality, is characterized by features like uncontrolled cell growth, resistance to cell death, angiogenesis, invasion, and metastasis. Several of these processes are controlled by DHHC-mediated S-palmitoylation of oncogenes or tumor suppressors, including growth factor receptors (e.g., EGFR), kinases (e.g., AKT), and transcription factors (e.g., β-catenin). Dynamic regulation of S-palmitoylation is also governed by protein depalmitoylases. These enzymes balance the cycling of palmitoylation and regulate cellular signaling, cell growth, and its organization. Given the significance of S-palmitoylation in cancer, the DHHCs and protein depalmitoylases are promising targets for cancer therapy. Here we summarize the catalytic mechanisms of DHHC enzymes and depalmitoylases, their role in cancer progression and prevention, as well as the crosstalk of palmitoylation with other post-translational modifications. Additionally, we discuss the methods to detect S-palmitoylation, the limitations of available DHHC-targeting inhibitors, and ongoing research efforts to address these obstacles.