STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice

Abstract

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 Cys 108 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.

NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation

“…In contrast, 2-BP potently suppressed caspase-1 and GSDMD cleavage ase well as IL-1β secretion in BMDMs activated by nigericin ( Figures S2B and S2C ), which is the typical readout of NLRP3 inflammasome activation, suggesting that 2-BP inhibited the activation step of the NLRP3 inflammasome. Additionally, MY-D4, a more recent improved inhibitor of ZDHHC enzymes, 37 , 38 also exhibited strong inhibition of caspase-1 and GSDMD cleavage ( Figure S2D ) in BMDMs, further confirming that ZDHHC inhibition could repress NLRP3 inflammasome activation. We also evaluated the effect of ZDHHC inhibitors on inflammasome activation in human macrophages, including THP-1 and human peripheral blood mononuclear cell (PBMC)-derived primary macrophages.…”