ABSTRACT
Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential therapeutic targets for GCs are urgently needed. Here we show that Actin-like protein 6 A (ACTL6A), encoding an SWI/SNF subunit, is highly expressed in GCs. ACTL6A is found to be critical for regulating the glutathione (GSH) metabolism pathway because it upregulates γ-glutamyl-cysteine ligase catalytic subunit (GCLC) expression, thereby reducing reactive oxygen species (ROS) levels and inhibiting ferroptosis, a regulated form of cell death driven by the accumulation of lipid-based ROS. Mechanistic studies show that ACTL6A upregulates GCLC as a cotranscription factor with Nuclear factor (erythroid-derived 2)-like 2 (NRF2) and that the hydrophobic region of ACTL6A plays an important role. Our data highlight the oncogenic role of ACTL6A in GCs and indicate that inhibition of ACTL6A or GCLC could be a potential treatment strategy for GCs.
Subject(s)
Ferroptosis , Stomach Neoplasms , Humans , Reactive Oxygen Species/metabolism , Stomach Neoplasms/genetics , Ferroptosis/genetics , Transcription Factors , Glutathione , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Actins , Chromosomal Proteins, Non-Histone/metabolism , DNA-Binding Proteins/metabolismABSTRACT
Metabolic reprogramming can contribute to colorectal cancer progression and therapy resistance. Identification of key regulators of colorectal cancer metabolism could provide new approaches to improve treatment and reduce recurrence. Here, we demonstrate a critical role for the COP9 signalosome subunit CSN6 in rewiring nucleotide metabolism in colorectal cancer. Transcriptomic analysis of colorectal cancer patient samples revealed a correlation between CSN6 expression and purine and pyrimidine metabolism. A colitis-associated colorectal cancer model established that Csn6 intestinal conditional deletion decreased tumor development and altered nucleotide metabolism. CSN6 knockdown increased the chemosensitivity of colorectal cancer cells in vitro and in vivo, which could be partially reversed with nucleoside supplementation. Isotope metabolite tracing showed that CSN6 loss reduced de novo nucleotide synthesis. Mechanistically, CSN6 upregulated purine and pyrimidine biosynthesis by increasing expression of PHGDH, a key enzyme in the serine synthesis pathway. CSN6 inhibited ß-Trcp-mediated DDX5 polyubiquitination and degradation, which in turn promoted DDX5-mediated PHGDH mRNA stabilization, leading to metabolic reprogramming and colorectal cancer progression. Butyrate treatment decreased CSN6 expression and improved chemotherapy efficacy. These findings unravel the oncogenic role of CSN6 in regulating nucleotide metabolism and chemosensitivity in colorectal cancer. SIGNIFICANCE: CSN6 deficiency inhibits colorectal cancer development and chemoresistance by downregulating PHGDH to block nucleotide biosynthesis, providing potential therapeutic targets to improve colorectal cancer treatment.
Subject(s)
Colorectal Neoplasms , Drug Resistance, Neoplasm , Humans , COP9 Signalosome Complex/genetics , COP9 Signalosome Complex/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Pyrimidines , Nucleotides , DEAD-box RNA HelicasesABSTRACT
Radiation proctopathy (RP) is characterized by inflammation of colorectal tissue and is a common complication of radiation therapy for pelvic malignancies with high incidence but lacking effective treatment. Here, we found that platelet-derived growth factor C (PDGF-C) and fibrosis markers were up-regulated in tissue samples from patients with RP and in rectal tissues after irradiation in a mouse model of RP. Genetic deletion of Pdgf-c in mice ameliorated RP-induced injuries. Genome-wide gene expression profiling and in vitro assays revealed that the promotive effect of PDGF-C in RP development was mediated by activation of PDGF receptors (PDGFRs) and C-X-C motif chemokine receptor 4, a proinflammatory chemokine regulated by transcription factor ETS variant transcription factor 1. Treatment with crenolanib, a selective inhibitor of PDGFRs, prevented or reduced RP in mice after irradiation. These results reveal that inhibition of PDGF-C signaling may have therapeutic value for the treatment of RP.
Subject(s)
Lymphokines , Platelet-Derived Growth Factor , Radiation Injuries/therapy , Rectum/pathology , Animals , Humans , Mice , Receptors, Platelet-Derived Growth Factor/metabolism , Rectum/radiation effects , Signal TransductionABSTRACT
BACKGROUND: Human are often simultaneously exposed to polycyclic aromatic hydrocarbons (PAHs) and metals, yet relatively little is known regarding their co-exposure effects on oxidative damage. Genetic factors and the gene-environment interactions can also determine the severity of oxidative damage. Four polymorphisms in microRNA (miRNA) genes (rs11614913, rs2292832, rs2910164, and rs3746444) have been well-studied to be associated with oxidative damage-related diseases. OBJECTIVE: To investigate the influences of PAH-metal co-exposure, four polymorphisms, and their interactions on oxidative damage levels. METHODS: We conducted a cross-sectional study in 1385 coke oven workers. We quantified exposure levels of PAHs and metals by urinary monohydroxy-PAHs, plasma benzo[a]pyrene-7,8-diol-9,10-epoxide-albumin adducts, and urinary metals, respectively, and measured oxidative damage levels by 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine. We also genotyped four polymorphisms. RESULTS: In multiple-pollutant models, 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were associated with multiple PAH exposure biomarkers, as well as with multiple metals (ptrendâ¯<â¯0.05). Metabolites of phenanthrene and pyrene interacted synergistically with lead and zinc to influence 8-iso-prostaglandin-F2α (ßinteractionâ¯>â¯7.75%, false discovery rate-adjusted pinteractionâ¯≤â¯2.25â¯×â¯10-5). Significantly higher 8-hydroxydeoxyguanosine was observed in carriers of rs11614913 CC variant homozygote than TC carriers (pâ¯=â¯0.037). Associations of the number of rs11614913 C allele with increased 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were significant (ßstdâ¯>â¯0, ptrendâ¯<â¯0.05) and more pronounced in workers with lower metals [p for modifying effect (pME) < 0.040]. Positive associations of some PAHs and metals with 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were weaker in carriers of rs11614913 CC genotype or C allele (pMEâ¯<â¯0.05). CONCLUSION: PAH-metal co-exposure, rs11614913, and their interactions may affect oxidative damage levels in Chinese population in a complex manner that are worthy of further investigation.