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Targeting SOX13 inhibits the assembly of respiratory chain supercomplexes to overcome ferroptosis-resistance in gastric cancer

ABSTRACT: Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines were constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines were identified. The expression of SOX13/SCAF1 was manipulated in GC cell lines where relevant biological and molecular analyses were performed. Molecular docking and computational screening were performed to screen potential inhibitors of SOX13. We showed that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics, NADPH production and chemo- and immune-resistance. Zanamivir, reverted the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Overall, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247870 | GEO | 2023/11/17

REPOSITORIES: GEO

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Targeting SOX13 inhibits the assembly of respiratory chain supercomplexes to overcome ferroptosis-resistance in gastric cancer

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RNA transcriptome sequencing analysis of SNU-668 Erastin-resistant cells transfected with shRNA-SOX13 or control shRNA

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Project description:Innate-like gd T effector subsets are exported from the thymus as “memory-like” cells prewired for rapid, specialized function. Previously, we showed that emergent gd subsets distinguished by TCRg and TCRd usage in the fetal and adult thymus possess distinct global transcriptomes and the subset-specific combinatorial expression of High Mobility Group box transcription factors (HMG TFs) shown as a primary determinant of gd effector differentiation. While the detailed mechanism of HMG TFs cooperativity and counter-regulations are not fully understood, a key feature for IL-17 producing gd T effectors (Tgd17) is predicted to be context-dependent interactions between SOX13 and TCF1 that result in diversified target gene regulation. More SOX13 allow more TCF1 dockings on DNA. TCF1 chromatin occupancy in the Tgd17 gene cluster (V2 set) mimics when the amount of SOX13 is enhanced like the Sox13 transgenic system. Globally 75% of SOX13 binding is overlapped with TCF1 binding and V2 set-specifically 85% of SOX13 targets are overlapped with TCF1 targets. The genome-wide analysis between TCF1 and SOX13 indicates cooperative and active SOX13-dependent-TCF1-modulations on V2 sets.

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Essential functions of the transcription factors TCF1 and SOX13 in gdT cell development (Sox13hi and Sox13lo)

Project description:Innate-like gd T effector subsets are exported from the thymus as “memory-like” cells prewired for rapid, specialized function. Previously, we showed that emergent gd subsets distinguished by TCRg and TCRd usage in the fetal and adult thymus possess distinct global transcriptomes and the subset-specific combinatorial expression of High Mobility Group box transcription factors (HMG TFs) shown as a primary determinant of gd effector differentiation. While the detailed mechanism of HMG TFs cooperativity and counter-regulations are not fully understood, a key feature for IL-17 producing gd T effectors (Tgd17) is predicted to be context-dependent interactions between SOX13 and TCF1 that result in diversified target gene regulation. More SOX13 allow more TCF1 dockings on DNA. TCF1 chromatin occupancy in the Tgd17 gene cluster (V2 set) mimics when the amount of SOX13 is enhanced like the Sox13 transgenic system. Globally 75% of SOX13 binding is overlapped with TCF1 binding and V2 set-specifically 85% of SOX13 targets are overlapped with TCF1 targets. Mostly V2 sets are H3K4me3 (79%) and the genome wide analysis between TCF1 and SOX13 indicate cooperative and active SOX13-dependent-TCF1-modulations on V2 sets.

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Quantitative proteomic analysis reveals maturation as a mechanism underlying glucocorticoid resistance in B lineage ALL and JNK inhibitors as a re-sensitising therapy

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