Oncometabolite succinylacetone activates HIF-1α signaling and promotes angiogenesis in GSTZ1-deficient HCC

We describe a unique regulation of the succinylacetone/PHD2/HIF-1α axis by a metabolic enzyme GSTZ1. The total RNA was isolated from HepG2 cells stably transfected with or without GSTZ1-KO and analyzed using RNA-seq. Our work demonstrates that GSTZ1-deficient promotes HCC angiogenesis through stabilizing HIF-1α due to succinylacetone accumulation. In addition, the combination of targeting HIF-1α and PD-L1 could limit tumorigenesis and progression for Gstz1-/-mice, thus providing a potential target for HCC therapy. To characterize GSTZ1-dependent global changes in the transcriptome under hypoxia, we conducted a genome-wide RNA sequencing (RNA-seq) analysis. First, we established GSTZ1 knockout (GSTZ1-KO) HepG2 cell lines using the CRISPR/Cas9 system. Total RNA was isolated from GSTZ1-KO and parental HepG2 cells (control) maintained under 1% O2 concentration for 12 h and subjected to sequencing.