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Patient-Specific Pharmacogenomics demonstrates xCT as Predictive Therapeutic Target in Colon Cancer with Possible Implications in Tumor Connectivity

ABSTRACT: Colorectal cancer (CRC) represents the third-leading cause of cancer-related deaths. Knowledge covering diverse cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present an in-depth comparative mRNA-seq analysis of tissue samples from 32 CRC patients, pairing tumors with adjacent healthy tissues. The differential expression gene (DEG) analysis revealed apparently dysregulated metabolic programs,in what we focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2 genes which compose the cystine/glutamate transporter (Xc-) system. To assess the oncogenic potency of the Xc- system in a cellular setting, we applied a knowledge-based approach for analyzing gene perturbations from CRISPR screens across various cell types as well as using a variety of functional assays in five primary patient-derived organoid cell models to functionally verify our hypothesis. We identified a previously undescribed cell surface protein signature predicting chemotherapy resistance and further highlighted the causality and potential of pharmacological blockage of ferroptosis as promising avenue for cancer therapy. Biological processes such as redox homeostasis, ion/amino acid transporters and regulators of neuronal survival and differentiation were associated with these co-dependent genes in patient specimens. This study highlights a number of potential clinical targets for CRC and promotes patient-individual in vitro model systems as functionally validate in silico predictions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305337 | GEO | 2025/09/21

REPOSITORIES: GEO

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The Deubiquitylase USP52 Regulates Cell Proliferation and Ferroptosis through Stabilizing SLC7A11/xCT in Bladder Cancer

Project description:Ferroptosis, a recently coined non-apoptotic form of cell death, is triggered by lethal accumulation of iron-dependent lipid peroxidation. SLC7A11/xCT, acts as a central hub in ferroptosis, is closely related to the development of multiple human diseases. However, the specific functions and potential regulatory mechanisms of ferroptosis, especially xCT protein, in bladder cancer (BLCA) remain poorly understood. Herein, through an unbiased siRNA screen targeting 96 deubiquitinases (DUBs), we identified USP52/PAN2 as a top regulator essential for xCT protein translational activity and ferroptosis process. Functionally, loss of USP52 inhibits glutathione (GSH) synthesis through xCT degradation, leading to elevated lipid peroxidation and ferroptosis, thereby suppresses BLCA progression. Mechanistically, USP52 physically interacts with xCT through its WD40 domain, biochemically hydrolyzes the K48-conjugated ubiquitin chains of xCT at K4 and K12, thereby promotes its protein stability. Importantly, USP52 expression demonstrates a positive correlation with xCT expression in clinical BLCA samples, and high USP52 expression is linked to a worse progression and prognosis. Additionally, USP52 depletion and IKE synergistically restrained the progression of BLCA by triggering ferroptosis in vivo. Collectively, our findings reveal a molecular mechanism of USP52-xCT axis in ferroptosis, and uncover a previously unappreciated role of USP52 in BLCA tumorigenesis.

2024-12-09 | GSE263111 | GEO

Genomic analysis of xCT-mediated regulatory network: identification of novel targets against AIDS-associated lymphoma

Project description:Kaposiâs sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the genomic gene profile altered by SASP treatment within 3 KSHV+ PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further functionally validate 2 downstream candidates, OSGIN1 (Oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), their relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these xCT-regulated novel downstream genes may help devise promising therapeutic strategies against PEL and/or other AIDS-related lymphoma. 3 KSHV PEL cell lines were treated with xCT selective inhibitor Sulfasalazine (SASP) and the gene expression signature was compared to that of untreated cells

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Inhibition of xCT Suppresses Melanoma progress

Project description:Tumor cells increase glutamate release through the cystine/glutamate transporter xCT to balance oxidative homeostasis in tumor cells and promote tumor progression. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine, SAS), approved by FDA for inflammatory diseases, or genetic knockdown induced ROS-related death in melanoma cells. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma.

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XCT is a novel regulator of chromatin functionally conserved across eukaryotes

Project description:XCT was originally identified due to the short circadian period observed in plants mutant for this gene. Proteins with homology to XCT are found across eukaryotes, but their molecular function is unknown. We have recently demonstrated that in Schizosaccharomyces pombe, the XCT ortholog Xap5 is a chromatin-associated protein that acts in a similar manner as the histone variant H2A.Z to suppress aberrant gene expression. Here, we demonstrate that although XCT and H2A.Z act in similar pathways to control plant development, XCT's role in the circadian clock is independent of H2A.Z.

2019-05-01 | GSE67813 | GEO

Genomic analysis of xCT-mediated regulatory network: identification of novel targets against AIDS-associated lymphoma

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2015-11-23 | GSE65418 | GEO

Role of the glial glutamate exchanger xCT in ventral hippocampus in resilience to stress

Project description:We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and established a previously unknown role for the glial marker xCT in the homeostatic regulation of the ventral dentate gyrus (vDG) in stress resilience and antidepressant responses. We provide RNAseq roadmap for the stress-sensitive vDG and show that the transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27acet, to negatively regulate xCT expression. Reduced xCT was also observed in a genetic mouse model of inherent susceptibility to depression. Pharmacologically modulating histone acetylation with next-generation therapeutics, such as acetyl-N-cysteine (NAC) or acetyl-L-carnitine (LAC), rapidly increased xCT reduction and activated a network that included mGlu2 receptors to prime an enhanced glutamate homeostasis that promoted stress resilience and antidepressant-like responses. Moreover, pharmacological xCT blockage counteracted NAC prophylactic effects. Anatomical (vDG) and cell-type specific (GFAP+) virus-overexpression mimicked the effects of pharmacological treatments in increasing stress resilience. These findings establish xCT as critical regulator of the glutamate system in a network with mGlu2 receptors. These studies also point to a role of histone acetylation as mediator of stress resilience.

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Targeting N-glycosylation of 4F2hc mediated by glycosyltransferases B3GNT3 sensitizes ferroptosis of pancreatic ductal adenocarcinoma

Project description:Aberrant glycosylation involves multifaceted pathological and pathophysiological changes in pancreatic ductal adenocarcinoma (PDAC), including but not limited to conferring tumor cells the ability to resist cell death. Ferroptosis driven by lethal lipid peroxidation provides a targetable vulnerability to PDAC. However, the crosstalk between glycosylation and ferroptosis remains unclear. Here, we identified 4F2hc, a subunit of the glutamate-cystine antiporter system Xc–, its N-glycosylation is involved in PDAC ferroptosis by N- and O-linked glycoproteomics. Knockdown of SLC3A2 (gene name of 4F2hc) or blocking the N-glycosylation of 4F2hc potentiates ferroptosis sensitization of PDAC cells by impairing the activity of system Xc– manifested by a marked decrease in intracellular glutathione. To identify which glycosyltransferases are critical for glycosylation initiation during ferroptosis execution. We collected 207 glycosyltransferase genes (GTGs) and performed parallel RNA-seq to reveal that the glycosyltransferase B3GNT3 catalyzes the glycosylation of 4F2hc, which stabilizes the 4F2hc protein as well as its interaction with xCT. Additionally, upon the combination with a ferroptosis inducer, treatment with the classical N-glycosylation inhibitor tunicamycin (TM) markedly triggered the overactivation of lipid peroxidation and enhanced the sensitivity of PDAC cells to ferroptosis. Notably, we confirmed that genetic perturbation of SLC3A2 or combination treatment with TM markedly increased ferroptosis sensitivity in the orthotopic PDAC model. Clinically, high expression of 4F2hc and B3GNT3 contributes to the progression and poor survival of PDAC patients. Collectively, our findings reveal a previously unappreciated function of N-glycosylation of 4F2hc in ferroptosis and suggest that targeting glycosylated 4F2hc can induce susceptibility to ferroptosis in PDAC.

2023-07-12 | GSE207741 | GEO

Microvirga tunisiensis strain:XCT-34

Project description:Microvirga tunisiensis strain:XCT-34 Genome sequencing

| PRJNA643673 | ENA

Inhibition of xCT Suppresses Melanoma progress

Project description:Inhibition of xCT Suppresses Melanoma progress

| PRJNA701281 | ENA

Patient-Specific Pharmacogenomics demonstrates xCT as Predictive Therapeutic Target in Colon Cancer with Possible Implications in Tumor Connectivity

Project description:Patient-Specific Pharmacogenomics demonstrates xCT as Predictive Therapeutic Target in Colon Cancer with Possible Implications in Tumor Connectivity

| PRJNA1305329 | ENA

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