Oncogenic features of KDM4A histone demethylase in mesothelioma
Moshe Lapidot, Raphael Bueno
Division of Thoracic Surgery, Lung Center and International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
Objectives: Malignant pleural mesothelioma (MPM) is a highly aggressive mesothelial derived cancer with a dismal median survival of 10.5 months. KDM4A functions as an epigenetic regulator and plays a critical role in transcription control, chromatin architecture and cellular differentiation. KDM4A is aberrantly expressed in various solid tumors and is involved in the regulation of tumor progression, but the role of KDM4A in MPM tumorigenesis and its underlying mechanism are unclear.
Methods: KDM4A protein,RNA expression and enzymatic activity were evaluated in human MPM cell lines and compared to normal LP9 mesothelial cells. The effects of KDM4A on transformation using specific shRNA were analyzed, specifically on cell growth, apoptosis, and cell cycle progression. Finally, KDM4A inhibitors were examined for their ability to specifically inhibit mesothelioma cell growth.
Results: We found KDM4A to be highly expressed in mesothelioma cell lines and human mesothelioma tumors both at mRNA and protein level. Silencing of KDM4A by RNA interference reduced cell growth (n=3, p<0.05) in MSTO-211H, H2804 and H2052 cells, relative to control cells and led to G1 cell cycle arrest. Furthermore, the down regulation of KDM4A serves as a key epigenetics inducer of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Finally, the genetic approach, was supported by pharmacological inhibition with KDM4A inhibitors which more efficiently inhibited cell growth (n=4) in H28 (EC50= 0.18 mM), MSTO-211H (EC50= 0.67 mM), H2804 (EC50= 0.18 mM) and H2052 (EC50= 0.33 mM) cells, compared to LP9 cells (EC50= 0.91 mM).
Conclusion: KDM4A overexpression is required for optimal cell growth in MPM thus encouraging further development of KDM4A inhibitors for clinical use to improve outcome in this devastating disease.
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