STAT3 palmitoylation increases dimerization, nuclear localization, and activation of target genes.

  • Major Finding: STAT3 palmitoylation increases dimerization, nuclear localization, and activation of target genes.

  • Mechanism: The palmitoyl acyltransferase ZDHHC19, amplified in many cancers, palmitoylates STAT3.

  • Impact: These findings highlight the potential importance of protein palmitoylation in cancer pathogenesis.

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The regulation of signal transducer and activator of transcription 3 (STAT3) is an important factor in immunity, inflammation, and cancer development. Niu, Sun, Chen, and colleagues discovered a previously unknown mechanism by which STAT3 is regulated: S-palmitoylation, the chemical linkage of a palmitoyl (C16) group to a cysteine residue. Pulse-chase experiments revealed that STAT3 palmitoylation is a dynamic process, and mutagenesis experiments suggested that the conserved cysteine residues C687 and C712 (in the SH2 domain) may underlie STAT3 palmitoylation. These cysteine residues are near a tyrosine residue (Y705) that is phosphorylated by Janus kinases, and phosphorylation of STAT3 induced by cytokines increased but was not required for STAT3 palmitoylation. In vitro experiments suggested that palmitoylation might regulate the dimerization of STAT3 independently of phosphorylation and acetylation. In a mouse model, consumption of a high-fat diet (HFD)—associated with an increase in free fatty acids and STAT3 activation—led to increased STAT3 palmitoylation and phosphorylation. The palmitoyl acyltransferase ZDHHC19 showed evidence of being the primary enzyme responsible for palmitoylating STAT3, and ZDHHC19 activity was required for activation of STAT3 induced by palmitic acid. Immunohistochemistry of 131 tumor samples from 85 patients with lung squamous cell carcinoma (LSCC) revealed that high ZDHHC19 protein levels correlated with nuclear STAT3 staining. Additionally, in an LSCC cell line grown into spheres, palmitic acid increased the number of spheres, sphere size, and stem-cell frequency. In a mouse xenograft model of LSCC, ZDHHC19 knockout reduced the tumor growth triggered by an HFD and reduced HFD-induced STAT3 palmitoylation, nuclear localization, and target gene expression, as well as decreasing Ki-67–positive proliferative tumor cells. Together, these results provide evidence that STAT3 palmitoylation, mediated by ZDHHC19, is an important regulator of STAT3 activity and may have an impact on LSCC and possibly other cancers.

Niu J, Sun Y, Chen B, Zheng B, Jarugumilli GK, Walker SR, et al. Fatty acids and cancer-amplified ZDHHC19 promote STAT3 activation through S-palmitoylation. Nature 2019;573:139–43.

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