Protein palmitoylation in cancer: molecular functions and therapeutic potential

Abstract

Protein S-palmitoylation (hereinafter referred to as protein palmitoylation) is a reversible lipid posttranslational modification catalyzed by the zinc finger DHHC-type containing (ZDHHC) protein family. The reverse reaction, depalmitoylation, is catalyzed by palmitoyl-protein thioesterases (PPTs), including acyl-protein thioesterases (APT1/2), palmitoyl protein thioesterases (PPT1/2), or alpha/beta hydrolase domain-containing protein 17A/B/C (ABHD17A/B/C). Proteins encoded by several oncogenes and tumor suppressors are modified by palmitoylation, which enhances the hydrophobicity of specific protein subdomains, and can confer changes in protein stability, membrane localization, protein-protein interaction, and signal transduction. The importance for protein palmitoylation in tumorigenesis has just started to be elucidated in the past decade; palmitoylation appears to affect key aspects of cancer, including cancer cell proliferation and survival, cell invasion and metastasis, and antitumor immunity. Here we review the current literature on protein palmitoylation in the various cancer types, and discuss the potential of targeting of palmitoylation enzymes or palmitoylated proteins for tumor treatment.

Keywords: cancer treatment; oncogene; protein S-palmitoylation; tumor suppressor; tumorigenesis.

Fig. 1

Schematic diagram of fatty acid metabolism to generate palmitic acid. Glucose is taken up by hepatocytes to generate pyruvate through glycolysis, and pyruvate is then catalyzed by pyruvate dehydrogenase in mitochondria to generate acetyl‐CoA. Next, acetyl‐CoA carboxylase catalyzes acetyl‐CoA to malonyl‐CoA. Finally, FASN exerts its multifunctional enzymatic activity to catalyze the formation of palmitic acid from acetyl‐CoA and malonyl‐CoA in multiple catalytic steps.

Fig. 2

The mechanisms of the palmitoylated proteins in human cancers. (A) Palmitoylation regulates the subcellular localization of proteins. A reduced level of palmitoylation might dissociate protein from plasma membrane to cytosol or nucleus. (B) Palmitoylation regulates the protein–protein interactions. Protein palmitoylation may enhance the binding affinity of modified protein with its binding partner on/by the plasma membrane. (C) Palmitoylation modulates the activation or inhibition of signaling pathways. The palmitoylation of numerous membrane protein may activate diversified downstream signaling to control not only cell survival, proliferation, and tumor progression. (D) Palmitoylation regulates protein stability. An altered level of protein palmitoylation might induce the enhanced level of ubiquitination or internalization for protein degradation. (E) Palmitoylation regulates exosome secretion. Protein palmitoylation is also involved in the biogenesis of multiple vesicle body (MVB) and the exosome secretion mediated by MVB. (F) Palmitoylation of Glut1 regulates glucose uptake and glycolysis; CD82 palmitoylation activates Src phosphorylation and inhibits angiogenesis; the palmitoylation of MC1R augments the synthesis of pigment; curcumin targeted inhibition of ZDHHC3 and lowers the level of ITGβ4 palmitoylation and inhibits cell migration. The blue areas on the cell membrane refer to lipid rafts, and the gray areas refer to nonlipid rafts.

Fig. 3

Schematic diagram of protein palmitoylation regulating tumor progression. Several oncogenes and tumor suppressors are modified by protein palmitoylation, a process that is dynamically controlled by the ZDHHC and PPT enzyme families, which add and remove palmitate, respectively. Palmitoylation affects protein stability, protein–protein interactions, membrane localization, and signaling transduction, thereby regulating tumor survival and tumor progression. Palmitoylation enzymes or palmitoylated proteins are potential targets for tumor treatment.