Fatty acids and cancer-amplified ZDHHC19 promote STAT3 activation through S-palmitoylation

• Published in: Nature (London) 2019-09, Vol.573 (7772), p.139-143
• Main Authors: Niu, Jixiao, Sun, Yang, Chen, Baoen, Zheng, Baohui, Jarugumilli, Gopala K., Walker, Sarah R., Hata, Aaron N., Mino-Kenudson, Mari, Frank, David A., Wu, Xu
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/105; 13/109; 13/51; 13/89; 13/95; 14/19; 38; 631/67; 631/80/86/2368; 631/92/2783; Acyltransferase; Acyltransferases - antagonists & inhibitors; Acyltransferases - chemistry; Acyltransferases - deficiency; Acyltransferases - metabolism; Amplification; Animals; Cancer; Carcinogenesis; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell fate; Chemical bonds; Conserved Sequence; Cysteine - metabolism; Cytokines; Deregulation; Dimerization; Disease Models, Animal; Fatty acids; Fatty Acids - metabolism; Grb2 protein; Growth factors; Health aspects; Heterografts; High fat diet; Homology; Humanities and Social Sciences; Humans; Immunity; In vivo methods and tests; Inflammation; Inflammation - metabolism; Inflammation - pathology; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-6 - immunology; Interleukin-6 - metabolism; Kinases; Letter; Lipids; Lipoylation; Lung carcinoma; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Metastasis; Mice; Mice, SCID; multidisciplinary; Mutation; Neoplasm Transplantation; Palmitoylation; Phosphorylation; Polyethylene glycol; Protein Multimerization; Proteins; Science; Science (multidisciplinary); Signal Transduction; Squamous cell carcinoma; src Homology Domains; Stat3 protein; STAT3 Transcription Factor - chemistry; STAT3 Transcription Factor - metabolism; Stimulation; Transcription activation; Transcription factors; Tumorigenesis; Tumors; Tyrosine
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1511-x

Signal transducer and activator of transcription 3 (STAT3) has a critical role in regulating cell fate, inflammation and immunity 1 , 2 . Cytokines and growth factors activate STAT3 through kinase-mediated tyrosine phosphorylation and dimerization 3 , 4 . It remains unknown whether other factors promote STAT3 activation through different mechanisms. Here we show that STAT3 is post-translationally S -palmitoylated at the SRC homology 2 (SH2) domain, which promotes the dimerization and transcriptional activation of STAT3. Fatty acids can directly activate STAT3 by enhancing its palmitoylation, in synergy with cytokine stimulation. We further identified ZDHHC19 as a palmitoyl acyltransferase that regulates STAT3. Cytokine stimulation increases STAT3 palmitoylation by promoting the association between ZDHHC19 and STAT3, which is mediated by the SH3 domain of GRB2. Silencing ZDHHC19 blocks STAT3 palmitoylation and dimerization, and impairs the cytokine- and fatty-acid-induced activation of STAT3. ZDHHC19 is frequently amplified in multiple human cancers, including in 39% of lung squamous cell carcinomas. High levels of ZDHHC19 correlate with high levels of nuclear STAT3 in patient samples. In addition, knockout of ZDHHC19 in lung squamous cell carcinoma cells significantly blocks STAT3 activity, and inhibits the fatty-acid-induced formation of tumour spheres as well as tumorigenesis induced by high-fat diets in an in vivo mouse model. Our studies reveal that fatty-acid- and ZDHHC19-mediated palmitoylation are signals that regulate STAT3, which provides evidence linking the deregulation of palmitoylation to inflammation and cancer. The palmitoylation of STAT3 is mediated by fatty acids and/or the palmitoyl acyltransferase ZDHHC19, and deregulation of this palmitoylation has a role in inflammation and tumorigenesis.