Protein palmitoylation and cancer

Abstract

Protein S-palmitoylation is a reversible post-translational modification that alters the localization, stability, and function of hundreds of proteins in the cell. S-palmitoylation is essential for the function of both oncogenes (e.g., NRAS and EGFR) and tumor suppressors (e.g., SCRIB, melanocortin 1 receptor). In mammalian cells, the thioesterification of palmitate to internal cysteine residues is catalyzed by 23 Asp-His-His-Cys (DHHC)-family palmitoyl S-acyltransferases while the removal of palmitate is catalyzed by serine hydrolases, including acyl-protein thioesterases (APTs). These enzymes modulate the function of important oncogenes and tumor suppressors and often display altered expression patterns in cancer. Targeting S-palmitoylation or the enzymes responsible for palmitoylation dynamics may therefore represent a candidate therapeutic strategy for certain cancers.

Keywords: S‐palmitoylation; lipid; lipidation; post‐translational modification; tumor.

Figure 1. The biochemistry of protein palmitoylation

(A) Palmitate (derived from palmitoyl‐CoA) can be thioesterified to substrate proteins by DHHC (Asp‐His‐His‐Cys)‐family protein S‐acyltransferases (PATs). DHHC PATs are integral membrane proteins (blue) with the active site oriented toward the cytosol. These enzymes catalyze palmitoylation on internal cysteine (Cys) residues of substrate proteins (S‐acylation). The DHHC enzyme is first autopalmitoylated on the DHHC cysteine residue with the release of free coenzyme A (CoA), followed by a transfer of the palmitate group to the acceptor cysteine residue of a substrate protein (purple). (B) Acylprotein thioesterase (APT, green) can remove palmitate groups from palmitoylated proteins (purple). APT1/2 are themselves palmitoylated and contain a hydrophobic pocket to accept palmitoylated substrates and position the substrate palmitoylated cysteine near the active site serine (Ser) residue.

Figure 2. A highly connected web of palmitoylation events

(A) ER‐resident ZDHHC6 can autopalmitoylate, like other DHHC family members. In addition, three cysteine residues within the C‐terminal tail of ZDHHC6 are palmitoylated by a distinct enzyme, ZDHHC16, representing a palmitoylation cascade. (B) The acylprotein thioesterase APT2, which itself requires palmitoylation to function normally, can remove the C‐terminal palmitoyl groups on ZDHHC6.

Figure 3. Many cancer drivers are palmitoylated

Bailey et al 69 identified a set of 299 cancer drivers, 78 of which are annotated in SwissPalm (Dataset 3) as being palmitoylated in at least one of fifteen proteomics studies. A subset of the most frequently identified proteins are shown in the box, indicating how many times they have been discovered as palmitoylated in high‐throughput studies (15 total).

Figure 4. Examples of protein palmitoylation and cancer

(A) The NRAS GTPase has a conserved C‐terminal CaaX motif that is farnesylated and O‐methylated (OMe), then palmitoylated by the Golgi‐resident ZDHHC9‐GOLGA7 complex. Dually lipidated NRAS is properly anchored in the plasma membrane. (B) SCRIB is localized to the plasma membrane by ZDHHC7‐catalyzed palmitoylation. SCRIB regulates the Hippo kinase cascade, ultimately phosphorylating YAP and TAZ, occluding them from the nucleus. (C) In response to ultraviolet (UV) radiation‐induced DNA damage, ATR phosphorylates ZDHHC13, activating it. ZDHHC13 palmitoylates MC1R, which can then drive cAMP‐dependent MITF transcriptional activation of melanin synthesis and DNA repair to mitigate DNA damage. Certain MC1R alleles, termed RHC variants, are found in cancer‐sensitive populations and have mutations that reduce MC1R palmitoylation. This results in downregulation of the DNA damage response and sensitization of the cells to damage. (D) Inositol‐1,4,5‐triphosphate (IP3) activates the receptor IP3R, a tetrameric Ca²⁺ channel, to stimulate calcium release. IP3R monomers are palmitoylated by a ZDHHC6‐SELENOK complex, with the selenocysteine (Sec) residue of SELENOK being essential to stabilize the autoacylated ZDHHC6 intermediate.