Diverse Roles of Protein Palmitoylation in Cancer Progression, Immunity, Stemness, and Beyond

Abstract

Protein S-palmitoylation, a type of post-translational modification, refers to the reversible process of attachment of a fatty acyl chain—a 16-carbon palmitate acid—to the specific cysteine residues on target proteins. By adding the lipid chain to proteins, it increases the hydrophobicity of proteins and modulates protein stability, interaction with effector proteins, subcellular localization, and membrane trafficking. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), whereas depalmitoylation is catalyzed by a family of acyl-protein thioesterases. Increasing numbers of oncoproteins and tumor suppressors have been identified to be palmitoylated, and palmitoylation is essential for their functions. Understanding how palmitoylation influences the function of individual proteins, the physiological roles of palmitoylation, and how dysregulated palmitoylation leads to pathological consequences are important drivers of current research in this research field. Further, due to the critical roles in modifying functions of oncoproteins and tumor suppressors, targeting palmitoylation has been used as a candidate therapeutic strategy for cancer treatment. Here, based on recent literatures, we discuss the progress of investigating roles of palmitoylation in regulating cancer progression, immune responses against cancer, and cancer stem cell properties.

Functional role of fatty acid synthase for signal transduction in Core binding factor-AML with activating c-Kit mutation

“…Intriguingly, cathepsins are also known to be overexpressed and associated with poor clinical outcome in pediatric [25]. Recent studies have suggested potential role for S-palmitoylation in lysosomal functions indirectly through its effects on proteins involved in lysosomal tra cking, membrane fusion, signaling pathways and protein degradation [39]. Hence, inhibition of FASN can downregulate CTSZ, which then leads to a reduced degradation of c-Kit and p-c-Kit.…”

Advances of Protein Palmitoylation in Tumor Cell Deaths

“…The etiology of these disruptions includes changes in membrane dynamics and protein localization, which are critical in cellular signaling and initiating apoptosis. Additionally, anomalies in ZDHHC enzyme function have been associated with the proliferation of cancer characteristics, including unrestrained cell growth, invasion, and metastasis [121]. These findings underscore the enzymes' dual capacities as potential oncogenes or tumor suppressors, contingent on the biological context, and spotlight the therapeutic promise of targeting palmitoylation pathways to restore regulated cell death and combat cancer progression [111,122].…”