S-palmitoylation: A novel player in cancer and its emerging therapeutic implications

Abstract

S-palmitoylation is a reversible post-translational lipid modification involving the covalent attachment of palmitic acid to cysteine residues, thereby regulating protein localization, stability, trafficking, and function. This dynamic process is orchestrated by palmitoyltransferases and depalmitoylating enzymes, which respond to both cellular and environmental cues. Central to this machinery are the ZDHHC family of S-acyltransferases and several classes of serine hydrolases, - including PPTs, APTs, and ABHD family members, which mediate the addition and removal of palmitoyl groups, respectively. Dysregulation of palmitoylation has been implicated in various disease contexts, particularly cancer. In this review, we summarize current knowledge of the palmitoylation network, with an emphasis on ZDHHC enzymes, their substrate specificity, and regulatory features. We also discuss the roles of depalmitoylating enzymes in maintaining palmitoylation homeostasis and briefly examine the emerging crosstalk between palmitoylation and other post-translational modifications. Special emphasis is placed on the roles of palmitoylation in cancer, where it contributes to tumor cell proliferation, metabolic adaptation, immune evasion, metastasis, and regulation of cell death. Transcriptomic profiling across 31 tumor types using TCGA data reveals heterogeneous expression patterns of ZDHHC enzymes, including several with tissue - or tumor-specific enrichment, suggesting the existence of context-dependent palmitoylation programs. Finally, we outline recent efforts to develop inhibitors targeting palmitoylation or depalmitoylation enzymes, highlighting their potential both as mechanistic tools and as candidates for anticancer therapy. Together, these insights underscore the multifaceted roles of palmitoylation in cancer and point to its integration into broader regulatory and therapeutic frameworks.

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