title: Decreased histone H2B monoubiquitination in malignant gastric carcinoma.
abstract: OBJECTIVE
  To investigate H2B monoubiquitination (uH2B) and H3K4 di- and tri-methylation (H3K4-2me, H3K4-3me) levels and their clinical significance in gastric cancer (GC).
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  uH2B displays differential IHC staining patterns corresponding to progressive stages of GC. uH2B may contribute to tumorigenesis and could be a potential therapeutic target.
authors.affiliation: Zi-Jing Wang, Jiang-Yan Lou, Jie Chen, Cong Liu, Lian-Di Guo, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, Department of Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Zi-Jing
authors.initials: ZJ
authors.lastname: Wang
authors.forename: Jing-Lin
authors.initials: JL
authors.lastname: Yang
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Jiang-Yan
authors.initials: JY
authors.lastname: Lou
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.forename: Lian-Di
authors.initials: LD
authors.lastname: Guo
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D016022:Case-Control Studies; D002454:Cell Differentiation; D015536:Down-Regulation; D005260:Female; D006657:Histones / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008745:Methylation; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D057149:Ubiquitinated Proteins / Q000032:analysis*; D054875:Ubiquitination
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D057149:Ubiquitinated Proteins
keywords: Epigenetics; Gastric cancer; H2B monoubiquination; Histone modification; Nuclear immunostaining