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

机译：脂肪酸和癌症放大的ZDHHC19通过S-棕榈酰化促进STAT3活化

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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.
机译：信号转导和转录激活因子3（STAT3）在调节细胞命运，炎症和免疫力方面起着至关重要的作用（1,2）。细胞因子和生长因子通过激酶介导的酪氨酸磷酸化和二聚化激活STAT3（3,4）。尚不清楚其他因素是否通过不同机制促进STAT3激活。在这里，我们显示STAT3在SRC同源性2（SH2）域上被翻译后S-棕榈酰化，从而促进STAT3的二聚化和转录激活。与细胞因子刺激协同作用，脂肪酸可以通过增强STAT3的棕榈酰化直接激活STAT3。我们进一步确定ZDHHC19为调节STAT3的棕榈酰基酰基转移酶。细胞因子刺激通过促进ZDHHC19与STAT3之间的缔合而增加STAT3棕榈酰化，这是由GRB2的SH3结构域介导的。沉默ZDHHC19会阻止STAT3棕榈酰化和二聚化，并损害细胞因子和脂肪酸诱导的STAT3激活。 ZDHHC19在多种人类癌症中频繁扩增，包括39％的肺鳞状细胞癌。高水平的ZDHHC19与患者样品中的高水平的核STAT3相关。另外，在肺鳞状细胞癌细胞中敲除ZDHHC19可以显着阻断STAT3活性，并在体内小鼠模型中抑制脂肪酸诱导的肿瘤球的形成以及高脂饮食诱导的肿瘤发生。我们的研究表明，脂肪酸和ZDHHC19介导的棕榈酰化是调节STAT3的信号，这提供了将棕榈酰化去调节与炎症和癌症联系起来的证据。

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  • 来源
    《Nature》 |2019年第7772期|139-143|共5页
  • 作者

    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;

  • 作者单位

    Harvard Med Sch Massachusetts Gen Hosp Cutaneous Biol Res Ctr Charlestown MA 02129 USA;

    Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|Harvard Med Sch Dept Med Boston MA 02115 USA|Univ New Hampshire Dept Mol Cellular & Biomed Sci Durham NH 03824 USA;

    Harvard Med Sch Dept Med Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Ctr Canc Charlestown MA USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Pathol Boston MA 02115 USA;

    Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|Harvard Med Sch Dept Med Boston MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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