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H2B monoubiquitination is a key epigenetic regulator of ferroptosis and is regulated by p53

ABSTRACT: H2B monoubiquitination (H2Bub1) is a key epigenetic modification that plays significant roles in multiple biological processes, although the global functions of H2Bub1 are still poorly understood. Ferroptosis is a newly identified form of non-apoptotic cell death whose regulatory mechanisms remain unclear. However, whether nuclear events participate in the regulation of ferroptosis is undetermined. Here, our study demonstrated that H2Bub1 levels are decreased during erastin treatment, and loss of H2Bub1 increases the cellular sensitivity to erastin-induced ferroptosis through epigenetically regulating the expression of SLC7A11, a key regulator of ferroptosis. Furthermore, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Functional studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1-mediated epigenetic pathway. Overall, our work uncovers an unappreciated epigenetic mechanism for the regulation of ferroptosis.

SUBMITTER: Dr. Su Chen

PROVIDER: S-SCDT-EMBOR-2018-47563V1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:To investigate H2B monoubiquitination (uH2B) and H3K4 di- and tri-methylation (H3K4-2me, H3K4-3me) levels and their clinical significance in gastric cancer (GC).Immunohistochemistry (IGC) was used to detect the differential levels of uH2B, H3K4-2me and H3K4-3me modifications in GC specimens from chemo/radiotherapy-naïve patients who underwent potentially curative surgical resection (n = 159) and in a random sampling of non-tumor gastric epithelium specimens (normal controls, n = 20). The immunohistochemistry (IHC)-detected modifications were classified as negative, low-level, or high-level using a dual-rated (staining intensity and percentage of positively-stained cells) semi-quantitative method. The relationships between uH2B modification levels and clinicopathological parameters of GC were assessed by a Wilcoxon rank sum test (pairwise comparisons) and the Kruskal-Wallis H test (multiple comparisons). The correlation between uH2B modification and survival was estimated by Kaplan-Meier analysis, and the role of uH2B as an independent prognostic factor for survival was assessed by multivariate Cox regression analysis.The presence and level of H3K4-2me and H3K4-3me IHC staining was similar between the normal controls and GC specimens. In contrast, the level of uH2B was significantly lower in the malignant gastric tissues (vs normal control tissues) and decreased along with increases in dedifferentiation (well differentiated > moderately differentiated > poorly differentiated). The level of uH2B correlated with tumor differentiation (P < 0.001), Lauren's diffuse- and intestinal-type classification (P < 0.001), lymph node metastasis (P = 0.049) and tumor-node-metastasis stage (P = 0.005). Patients with uH2B+ staining had higher 5-year survival rates than patients with uH2B-staining (52.692 ± 2.452 vs 23.739 ± 5.207, P < 0.001). The uH2B level was an independent prognostic factor for cancer-specific survival (95%CI: 0.237-0.677, P = 0.001).uH2B displays differential IHC staining patterns corresponding to progressive stages of GC. uH2B may contribute to tumorigenesis and could be a potential therapeutic target.

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H2B monoubiquitination is a key epigenetic regulator of ferroptosis and is regulated by p53

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