Available online 17 January 2024, 101054

High SIRT7 expression linked to survival of sorafenib-treated patients with HCC

Inhibition of SIRT7 combined with sorafenib synergistically restores sorafenib sensitivity in vitro and in vivo

SIRT7 regulates pro-survival ERK1/2 signalling through DDX3X epigenetic modification

Inhibition of SIRT7/DDX3X axis suppresses ERK1/2 signaling via NLPR3 inflammasome induced IL-1β disruption

Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance.

Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib.

SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1β inhibition.

SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

Dulbecco’s Modified Eagle Medium (DMEM)

eukaryotic initiation factor 2α

extracellular signaling-regulated kinase1/2

gene set enrichment analysis

liquid chromatography with tandem mass spectrometry

liver hepatocellular carcinoma

3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide

phosphorylated ERK1/2

radioimmunoprecipitation assay

The Cancer Genome Atlas

hepatocellular carcinoma

sorafenib resistance

SIRT7 inhibitor

ERK1/2 phosphorylation

DDX3X

© 2024 The Authors. Published by Elsevier Ltd.