Osteosarcoma is an aggressive malignancy with poor prognosis. Super-enhancers (SE) have been highlighted as critical oncogenic elements required for maintaining the cancer cell characteristics. However, the regulatory role of SEs in osteosarcoma properties has not yet been elucidated. In the current study, we found that osteosarcoma cells and clinical specimens shared a significant fraction of SEs. Moreover, leukemia-inhibitory factor (LIF) was identified as an essential factor under the control of osteosarcoma-specific SE. The expression of LIF was positively correlated with the stem cell core factor genes in osteosarcoma. Furthermore, LIF recombinant protein-treated osteosarcoma cells displayed enhanced stem cell-like characteristics, such as increased sphere-forming potential, stimulated self-renewal, upregulated metastasis ability, and increased stemness-related gene expression. Notably, the histone 3 lysine 27 tri-methylation (H3K27me3) demethylase UTX was found as a key activator of LIF transcription in osteosarcoma. The UTX inhibitor, GSK-J4, induced H3K27me3 accumulation and impaired histone 3 lysine 27 acetylation (H3K27ac) at LIF gene locus, leading to LIF signaling pathway inhibition. GSK-J4 treatment resulted in profound defects in stem cell-like characteristics and stemnessrelated gene activation in osteosarcoma by modulating the H3K27ac of NOTCH1 signaling pathway gene loci. The NOTCH1 inhibitor Crenigacestat (TargetMol, T3633) repressed LIF-mediated activation of the stemness-related genes in osteosarcoma patient-derived primary tissues.Implications: This study reveals osteosarcoma SE profiles and uncovers a distinct tumor-stemness epigenetic regulatory mechanism in which an osteosarcoma-specific SE-mediated factor, LIF, promotes osteosarcoma stemness gene activation via NOTCH1 signaling pathway.
BackgroundNuclear factor E2-related factor 2 (Nrf2) plays an anti-oxidative and phase II detoxification function via its up-regulation on various antioxidant response elements (ARE) genes. Nrf2 can protect both normal and cancer cells from damages of cell stress, thereby exerting a critical role in the development of cancer. The expression and significance of Nrf2 in gastric cancer, however, has not been reported. This study thus aimed to investigate the expression of Nrf2 in gastric cancer tissues via immunohistochemical (IHC) staining.Material/MethodsGastric carcinoma tissues from a total of 175 patients during surgical resection were examined for Nfr2 expression profiles using IHC staining on paraffin-embedded slides. Between-group-comparisons were performed by chi-square, Fisher’s exact, or Mann-Whitney U test. The correlation between Nfr2 expression and clinical indexes was further analyzed by Kaplan-Meier test, univariate/multivariate analysis, and log-rank test.ResultsNrf2 is mainly expressed in nuclei of gastric carcinoma tissues, with significant correlation with clinical indexes, including tumor size, invasive depth, lymph node metastasis, and invasion. Patients with Nrf2-positive expression had significantly lower survival rates compared to those in the negative group (p<0.01), with chemo-resistance against 5-fluorouracil (5-FU) (p<0.05).ConclusionsNrf2 expression is positively correlated with invasive gastric cancer, suggesting its utility as a predictive index for unfavorable prognosis.
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