A5111351855- Renal cell carcinoma treatment
- Renal and related cancers
- Ferroptosis and cancer prognosis
- Ovarian cancer diagnosis and treatment
- Liver physiology and pathology
- Epigenetics and DNA Methylation
- Obesity, Physical Activity, Diet
- Bariatric Surgery and Outcomes
- Gestational Diabetes Research and Management
- Mesenchymal stem cell research
- Rocket and propulsion systems research
- Nuclear Engineering Thermal-Hydraulics
- Connexins and lens biology
- Neuroscience and Neural Engineering
- Advanced Cellulose Research Studies
- Tissue Engineering and Regenerative Medicine
- Autophagy in Disease and Therapy
- Cancer, Hypoxia, and Metabolism
- RNA modifications and cancer
- Plant-derived Lignans Synthesis and Bioactivity
- Biofuel production and bioconversion
- Burn Injury Management and Outcomes
- Electrospun Nanofibers in Biomedical Applications
- Effects of Radiation Exposure
- Prostate Cancer Treatment and Research
Ruijin Hospital
2024-2025
Jiangyin People's Hospital
2024
Xuzhou Medical College
2024
Soochow University
2024
Zhujiang Hospital
2023-2024
Southern Medical University
2023-2024
Beijing Sport University
2024
Shanghai Jiao Tong University
2024
Nanjing Forestry University
2023
Nanjing University of Chinese Medicine
2023
Abstract Ferroptosis inducers have shown therapeutic potential in prostate cancer (PCa), but tumor heterogeneity poses a barrier to their efficacy. Distinguishing the regulators orchestrating metabolic crosstalk between cells could shed light on strategies more robustly activate ferroptosis. Here, we found that aberrant accumulation of jumonji domain containing 6 (JMJD6) proteins correlated with poorer prognosis PCa patients. Mechanistically, PCa-associated speckle type BTB/POZ protein...
<div>Abstract<p>Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in tumors. The screen identified chromodomain helicase DNA-binding protein 6 (CHD6) as essential regulator of the growth FH-mutated RCC. Mechanically, FH loss induced fumarate-mediated succinylation inactivation...
<p>Characteristics of patients whose tumors were used for PDOs or PDXs experiments, Related to Figure 4&7.</p>
<p>Supplementary Figure 2. FH deficiency accumulates CHD6 via inactivating Keap1, related to 2&3. A. WB and co-IP analysis indicating no interactions between VHL proteins in WCLs of ACHN cells. B. (left) RT-qPCR (right) indicated the protein or mRNA levels control VHL-depleted RCC C. Schematic illustration Keap1 deletion mutants. The binding capacity is with symbol. D. Western blots showing vitro ubiquitination assays conducted by incubating reconstituted Keap1–CUL3–RBX1 E3...
<p>Summary of the epigenetic regulators showing decreased sgRNA abundance in UOK-262 and ACHN cells, respectively.</p>
<p>Supplementary Figure 5. CHD6/SMARCA2/4-coordinated SEs-promoter looping boosts the transcription of NF-κB-related targets, related to 6. A. 3C assay indicated genes in WT, CHD6-KO Caki-2 cells with or without DMF stimulation. “Pro” means input-pro, while “3C” primers targeting enhancer region. B. ChIP-qPCR H3K27ac markers promoters enhancers CCL2, ICAM1, BCL3 gene UOK-262 (n = 5). C. Immunoblotting analysis p65 immunoprecipitates CHD6 depletion. D. SMARCA2/4 SEs 5) restoration. E....
<p>Identification of super-enhancer-associated genes in DMF-treated ACHN cells, related to Figure 6.</p>
<p>Oligonucleotides, related to Methods.</p>
<p>Supplementary Figure 1. Library and cells used for in vivo epigenetic CRISPR screen, related to A. Schematic diagram of FH mutations distributions the indicated protein domains. B. Intracellular fumarate levels were measured a panel RCC cell lines. C. Lorenz curve showing distribution sgRNAs epigenetic-focused library. D. Workflow generation UOK- or ACHN-clones without Cas9 evaluating guides that persist upon tumour formation from initiating (TICs), with further screens. E. Western...
<p>Supplementary Figure 4. CHD6 activates NF-κB signaling to potentiate FH-deficient RCC malignancy, related 5. A. Volcano plot showing differentially expressed genes in UOK-262 cells upon knockdown. B. Unsupervised cluster analysis of control and knockdown cells. C. ATAC-seq signals the profiles OCRs across indicated peaks UOK262 with versus without D. Heatmap exhibiting significance transcription factor motifs enriched accessible loci derived from CHD6-KD motif is dominantly...
<p>Supplementary Figure 6. In vitro and in vivo assessment of AU-15330 efficacy against FH-deficient RCC multiple preclinical models, related to 7. A. Dose-response curves IC50 FH-intact or cells treated with AU-15330. B. UOK-262 AU-15330, AU-15139, AU-16235. C-D. Mouse weight changes measurements (C) (n = 5) complete blood counts (D) performed on vehicle control mice as Fig. 7A. E. Representative HE graphs showing the morphology critical organs an increased amount F. FH-mutated...
<p>Supplementary Figure 3. CHD6 is essential for FH-deficient RCC cells, related to 4. A-B. MTT analysis of FH-WT PRCC (A) or canonical ccRCC (B) cells with without CHD6-KD. C. Competition-based assay measure the effect CHD4 shRNA on growth UOK-262 (n = 3 per time point). CHD4-KD were identified by coexpression green fluorescent protein (GFP) (LMN vector). The percentage GFP+ was thus tracked over 12 days and normalized GFP day 2. D. Quantified BIL signals orthotopic (FH-intact Caki-2)...
<p>Supplementary Figure 1. Library and cells used for in vivo epigenetic CRISPR screen, related to A. Schematic diagram of FH mutations distributions the indicated protein domains. B. Intracellular fumarate levels were measured a panel RCC cell lines. C. Lorenz curve showing distribution sgRNAs epigenetic-focused library. D. Workflow generation UOK- or ACHN-clones without Cas9 evaluating guides that persist upon tumour formation from initiating (TICs), with further screens. E. Western...
<p>Supplementary Figure 4. CHD6 activates NF-κB signaling to potentiate FH-deficient RCC malignancy, related 5. A. Volcano plot showing differentially expressed genes in UOK-262 cells upon knockdown. B. Unsupervised cluster analysis of control and knockdown cells. C. ATAC-seq signals the profiles OCRs across indicated peaks UOK262 with versus without D. Heatmap exhibiting significance transcription factor motifs enriched accessible loci derived from CHD6-KD motif is dominantly...
<p>Supplementary Figure 6. In vitro and in vivo assessment of AU-15330 efficacy against FH-deficient RCC multiple preclinical models, related to 7. A. Dose-response curves IC50 FH-intact or cells treated with AU-15330. B. UOK-262 AU-15330, AU-15139, AU-16235. C-D. Mouse weight changes measurements (C) (n = 5) complete blood counts (D) performed on vehicle control mice as Fig. 7A. E. Representative HE graphs showing the morphology critical organs an increased amount F. FH-mutated...
<p>Characteristics of patients whose tumors were used for PDOs or PDXs experiments, Related to Figure 4&7.</p>
<p>Supplementary Figure 5. CHD6/SMARCA2/4-coordinated SEs-promoter looping boosts the transcription of NF-κB-related targets, related to 6. A. 3C assay indicated genes in WT, CHD6-KO Caki-2 cells with or without DMF stimulation. “Pro” means input-pro, while “3C” primers targeting enhancer region. B. ChIP-qPCR H3K27ac markers promoters enhancers CCL2, ICAM1, BCL3 gene UOK-262 (n = 5). C. Immunoblotting analysis p65 immunoprecipitates CHD6 depletion. D. SMARCA2/4 SEs 5) restoration. E....
<p>Supplementary Figure 2. FH deficiency accumulates CHD6 via inactivating Keap1, related to 2&3. A. WB and co-IP analysis indicating no interactions between VHL proteins in WCLs of ACHN cells. B. (left) RT-qPCR (right) indicated the protein or mRNA levels control VHL-depleted RCC C. Schematic illustration Keap1 deletion mutants. The binding capacity is with symbol. D. Western blots showing vitro ubiquitination assays conducted by incubating reconstituted Keap1–CUL3–RBX1 E3...
<p>Identification of super-enhancer-associated genes in DMF-treated ACHN cells, related to Figure 6.</p>
<p>Summary of the epigenetic regulators showing decreased sgRNA abundance in UOK-262 and ACHN cells, respectively.</p>
<p>Supplementary Figure 3. CHD6 is essential for FH-deficient RCC cells, related to 4. A-B. MTT analysis of FH-WT PRCC (A) or canonical ccRCC (B) cells with without CHD6-KD. C. Competition-based assay measure the effect CHD4 shRNA on growth UOK-262 (n = 3 per time point). CHD4-KD were identified by coexpression green fluorescent protein (GFP) (LMN vector). The percentage GFP+ was thus tracked over 12 days and normalized GFP day 2. D. Quantified BIL signals orthotopic (FH-intact Caki-2)...
<p>Oligonucleotides, related to Methods.</p>
Small cell lung cancer (SCLC) is a highly malignant characterized by metastasis and an extremely poor prognosis. Although combined chemoimmunotherapy improves the prognosis of extensive-stage (ES)-SCLC, survival benefits remain limited. Furthermore, no reliable biomarker available so far to predict treatment outcomes for chemoimmunotherapy.This retrospective study included patients with ES-SCLC treated first-line atezolizumab or durvalumab standard chemotherapy between Janauray 1, 2019...