Dataset Information

Lysine-specific demethylase 1 promotes tumorigenesis and predicts prognosis in gallbladder cancer.

ABSTRACT: Gallbladder Cancer (GBC), characterized by invasive growth and infiltrative dissemination, is difficult to diagnose and has poor prognosis. Emerging evidence demonstrates that Lysine-Specific Demethylase 1 (LSD1) has important roles in carcinogenesis, proliferation and metastasis. We studied the roles and molecular mechanisms of LSD1 in GBC. We examined LSD1 expression in 109 paired samples of GBC and normal gallbladder tissues. We found GBC tissues had upregulated LSD1 compared with normal gallbladder tissues (P = 0.003), and its high expression was associated with tumor-node-metastasis stage (P < 0.0001), Nevin's stage (P = 0.0093) and distant metastases (P = 0.0070). We found positive correlations between LSD1 expression and other proteins: epithelial-mesenchymal transition markers, C-myc and cyclin-related proteins. Inhibiting LSD1 expression in vitro impaired the proliferation and invasiveness of GBC cells and also downregulated c-myc expression and consequently inhibited GBC cell proliferation. LSD1 overexpression promotes GBC development and may be a predictor for a worsened prognosis. LSD1 may be a novel therapeutic target and prognostic tool for gallbladder cancer.

SUBMITTER: Lian SX

PROVIDER: S-EPMC4741749 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lysine-specific demethylase 1 promotes tumorigenesis and predicts prognosis in gallbladder cancer.

Lian Shi Xian SX Shao Ye Bo YB Liu Hou Bao HB He Jun Yi JY Lu Wei Qi WQ Zhang Yong Y Jiang Ying Y Zhu Jun J

Oncotarget 20151001 32

Gallbladder Cancer (GBC), characterized by invasive growth and infiltrative dissemination, is difficult to diagnose and has poor prognosis. Emerging evidence demonstrates that Lysine-Specific Demethylase 1 (LSD1) has important roles in carcinogenesis, proliferation and metastasis. We studied the roles and molecular mechanisms of LSD1 in GBC. We examined LSD1 expression in 109 paired samples of GBC and normal gallbladder tissues. We found GBC tissues had upregulated LSD1 compared with normal gall ...[more]

PMID: 26460616

Similar Datasets

Project description:Introduction: Epigenetic-targeted therapy has been increasingly applied in the treatment of cancers. Lysine (K)-specific demethylase 6B (KDM6B) is an epigenetic enzyme involved in the coordinated control between cellular intrinsic regulators and the tissue microenvironment whereas the pan-cancer analysis of KDM6B remains unavailable. Methods: The dual role of KDM6B in 33 cancers was investigated based on the GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) databases. TIMER2 and GEPIA2 were applied to investigate the KDM6B levels in different subtypes or stages of tumors. Besides, the Human Protein Atlas database allowed us to conduct a pan-cancer study of the KDM6B protein levels. GEPIA2 and Kaplan-Meier plotter were used for the prognosis analysis in different cancers. Characterization of genetic modifications of the KDM6B gene was analyzed by the cBioPortal. DNA methylation levels of different KDM6B probes in different TCGA tumors were analyzed by MEXPRESS. TIMER2 was applied to determine the association of the KDM6B expression and immune infiltration and DNA methyltransferases. Spearman correlation analysis was used to assess the association of the KDM6B expression with TMB (tumor mutation burden) and MSI (microsatellite instability). The KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis and GO (Gene ontology) enrichment analysis were used to further investigate the potential mechanism of KDM6B in tumor pathophysiology. Results: KDM6B was downregulated in 11 cancer types and upregulated across five types. In KIRC (kidney renal clear cell carcinoma) and OV (ovarian serous cystadenocarcinoma), the KDM6B level was significantly associated with the pathological stage. A high level of KDM6B was related to poor OS (overall survival) outcomes for THCA (thyroid carcinoma), while a low level was correlated with poor OS and DFS (disease-free survival) prognosis of KIRC. The KDM6B expression level was associated with TMB, MSI, and immune cell infiltration, particularly cancer-associated fibroblasts, across various cancer types with different correlations. Furthermore, the enrichment analysis revealed the relationship between H3K4 and H3K27 methylation and KDM6B function. Conclusion: Dysregulation of the DNA methyltransferase activity and methylation levels of H3K4 and H3K27 may involve in the dual role of KDM6B in tumorigenesis and development. Our study offered a relatively comprehensive understanding of KDM6B's dual role in cancer development and response to immunotherapy.

Project description:We have previously demonstrated that crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) facilitates breast cancer proliferation. However, the underlying mechanisms are largely unknown. Here, we report that expression of HDAC5 and LSD1 proteins were positively correlated in human breast cancer cell lines and tissue specimens of primary breast tumors. Protein expression of HDAC5 and LSD1 was significantly increased in primary breast cancer specimens in comparison with matched-normal adjacent tissues. Using HDAC5 deletion mutants and co-immunoprecipitation studies, we showed that HDAC5 physically interacted with the LSD1 complex through its domain containing nuclear localization sequence and phosphorylation sites. Although the in vitro acetylation assays revealed that HDAC5 decreased LSD1 protein acetylation, small interfering RNA (siRNA)-mediated HDAC5 knockdown did not alter the acetylation level of LSD1 in MDA-MB-231 cells. Overexpression of HDAC5 stabilized LSD1 protein and decreased the nuclear level of H3K4me1/me2 in MDA-MB-231 cells, whereas loss of HDAC5 by siRNA diminished LSD1 protein stability and demethylation activity. We further demonstrated that HDAC5 promoted the protein stability of USP28, a bona fide deubiquitinase of LSD1. Overexpression of USP28 largely reversed HDAC5-KD-induced LSD1 protein degradation, suggesting a role of HDAC5 as a positive regulator of LSD1 through upregulation of USP28 protein. Depletion of HDAC5 by shRNA hindered cellular proliferation, induced G1 cell cycle arrest, and attenuated migration and colony formation of breast cancer cells. A rescue study showed that increased growth of MDA-MB-231 cells by HDAC5 overexpression was reversed by concurrent LSD1 depletion, indicating that tumor-promoting activity of HDAC5 is an LSD1 dependent function. Moreover, overexpression of HDAC5 accelerated cellular proliferation and promoted acridine mutagen ICR191-induced transformation of MCF10A cells. Taken together, these results suggest that HDAC5 is critical in regulating LSD1 protein stability through post-translational modification, and the HDAC5-LSD1 axis has an important role in promoting breast cancer development and progression.

Dataset Information

Lysine-specific demethylase 1 promotes tumorigenesis and predicts prognosis in gallbladder cancer.

Publications

Lysine-specific demethylase 1 promotes tumorigenesis and predicts prognosis in gallbladder cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets