STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice
Menée à l'aide d'une lignée de carcinome hépatocellulaire, d'échantillons tumoraux d'origine humaine et de modèles murins, cette étude met en évidence un mécanisme par lequel la palmitylation du facteur de transcription STAT3 favorise la croissance tumorale en induisant une boucle de régulation positive
Résumé en anglais
Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A, which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7, which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer. Liver tumor growth in mice is exacerbated by a feed-forward loop triggered by the palmitoylation of STAT3. Signaling by the transcription factor STAT3 promotes hepatocellular carcinoma (HCC). S-palmitoylation of STAT3, a reversible posttranslational modification mediated by DHHC palmitoyltransferases, increases its transcriptional activity. Jiang et al. investigated the effect of S-palmitoylation on liver tumor growth in mice. Bioinformatics analysis revealed an association between DHHC7 and HCC malignancy. DHHC7 stimulated STAT3 activity and HCC cell proliferation. The kinase CDK5 and the transcription factor HIF1α are associated with decreased survival in HCC, and ZDHHC7 expression was driven by HIF1α, a target of STAT3 that is stabilized by CDK5. Targeting this signaling loop reduced tumor growth in mice, supporting the therapeutic potential of disrupting this pathway. —Amy E. Baek
