ABSTRACT
Purpose: To study the role of lysine-specific demethylase 1 (LSD1) in retinoblastoma (RB) growth and to determine whether the LSD1 inhibitor SP2509 can inhibit RB progression. Methods: We detected the levels of LSD1 in 12 RB tissue samples, two RB cell lines (Y79 and Weri-RB1), and a retinal pigment epithelium cell line (ARPE-19). Overexpression or knockdown of LSD1 was performed to examine the role of LSD1 in RB cancer cell survival. In vitro and in vivo experiments were conducted to detect the antitumor effect of SP2509, and the antitumor mechanism of SP2509 was examined by RNA sequencing and Western blot. Results: LSD1 is overexpressed in RB tissues and cells and increases RB cancer cell viability and colony formation ability. The LSD1 inhibitor SP2509 inhibits RB cell proliferation in vitro and in vivo. Treatment with SP2509 increases the levels of dimethylated histone 3 lysine 4 (H3K4me2) and inhibits the expression of ß-catenin signaling pathway-related proteins in RB cells. Conclusions: We demonstrated that LSD1 is overexpressed in RB cells and promotes RB cell survival. The LSD1 inhibitor SP2509 exerted strong growth inhibition in vitro and in vivo, which was at least partially mediated by suppression of the ß-catenin pathway.
Subject(s)
Retinal Neoplasms , Retinoblastoma , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Histone Demethylases/genetics , Humans , Hydrazines , Lysine , Retinal Neoplasms/metabolism , Retinoblastoma/metabolism , Signal Transduction , Sulfonamides , beta Catenin/metabolismABSTRACT
Retinoblastoma (RB) is the most common intraocular malignant tumour in infants, and chemotherapy has been the primary therapy method in recent years. PRMT5 is an important member of the protein arginine methyltransferase family, which plays an important role in various tumours. Our study showed that PRMT5 was overexpressed in retinoblastoma and played an important role in retinoblastoma cell growth. EPZ015666 is a novel PRMT5 inhibitor, and we found that it inhibited retinoblastoma cell proliferation and led to cell cycle arrest at the G1 phase. At the same time, EPZ015666 regulated cell cycle related protein (P53, P21, P27, CDK2) expression. In brief, our study showed that PRMT5 promoted retinoblastoma growth, the PRMT5 inhibitor EPZ015666 inhibited retinoblastoma in vitro by regulating P53-P21/P27-CDK2 signaling pathways and slowed retinoblastoma growth in a xenograft model.
Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Isoquinolines/therapeutic use , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Pyrimidines/therapeutic use , Retinal Neoplasms/drug therapy , Retinoblastoma/drug therapy , Animals , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Immunohistochemistry , Male , Mice , Mice, Nude , Protein-Arginine N-Methyltransferases/metabolism , Real-Time Polymerase Chain Reaction , Retinal Neoplasms/enzymology , Retinal Neoplasms/pathology , Retinoblastoma/enzymology , Retinoblastoma/pathology , Tetrazolium Salts , Thiazoles , Time Factors , Transplantation, HeterologousABSTRACT
Retinoblastoma (RB) is the most common intraocular cancer in children, and chemotherapy has been the first-line treatment. However, due to the side effects of chemotherapy drugs, novel treatments must be developed. JQ1, a selective inhibitor of BRD4, suppresses cell growth in several cancers in which BRD4 is overexpressed. In the present study, BRD4 was overexpressed in retinoblastoma, and JQ1 effectively inhibited RB cell proliferation and colony formation by inducing cell cycle arrest and promoting apoptosis. Furthermore, the Myc-P21-CDK2 and Myc-cyclinD3/CDK6 pathways were activated in RB cells treated with JQ1, and an animal experiment suggested that JQ1 significantly inhibited tumour growth in vivo. In conclusion, JQ1 may be a potential drug treatment for retinoblastoma.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Azepines/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle/drug effects , Retinal Neoplasms/pathology , Retinoblastoma/pathology , Transcription Factors/antagonists & inhibitors , Triazoles/pharmacology , Animals , Blotting, Western , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival , Gene Expression Regulation, Neoplastic/physiology , Humans , Immunohistochemistry , Male , Mice , Mice, Nude , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Retinal Neoplasms/genetics , Retinal Pigment Epithelium/drug effects , Retinoblastoma/genetics , Signal Transduction , Transcription Factors/geneticsABSTRACT
Retinoblastoma (RB) is the most common type of intraocular malignant tumor that occurs in childhood. AR-42, a member of a newly discovered class of phenylbutyrate-derived histone deacetylase inhibitors, exerts antitumor effects on many cancers. In the present study, we initially evaluated the effect of AR-42 towards RB cells and explored the underlying mechanism in this disease. Our results found that AR-42 showed powerful antitumor effects at low micromolar concentrations by inhibiting cell viability, blocking cell cycle, stimulating apoptosis in vitro, and suppressing RB growth in a mouse subcutaneous tumor xenograft model. Furthermore, the AKT/nuclear factor-kappa B signaling pathway was disrupted in Y79 cells treated with AR-42. In conclusion, we propose that AR-42 might be a promising drug treatment for RB.
