Ramakrishnan, S.; Granger, V.; Rak, M.; Hu, Q.; Attwood, K.; Aquila, L.; Krishnan, N.; Osiecki, R.; Azabdaftari, G.; Guru, K.; Chatta, G.; Gueron, G.; McNally, L.; Ohm, J.; Wang, J.; Woloszynska, A. "Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer" (2019) Cell Death and Differentiation
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Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose Non-Fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of Zeste Homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2-based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death. We reveal a novel mechanism of action of EZH2 inhibition, alone and in combination with cisplatin, which induces immune signaling with the largest changes observed in interferon gamma (IFN-γ). This upregulation is a result of activated natural killer (NK) signaling as demonstrated by the increase in NK cell-associated genes MIP-1α, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors. Conversely, EZH2 inhibition results in decreased expression of pluripotency markers, ALDH2 and CK5, and increased cell death. Our results reveal a novel sensitivity of muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations to EZH2 inhibition alone and in combination with cisplatin. This sensitivity is mediated through increased NK cell-related signaling resulting in tumor cell differentiation and cell death. © 2019, ADMC Associazione Differenziamento e Morte Cellulare.


Documento: Artículo
Título:Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer
Autor:Ramakrishnan, S.; Granger, V.; Rak, M.; Hu, Q.; Attwood, K.; Aquila, L.; Krishnan, N.; Osiecki, R.; Azabdaftari, G.; Guru, K.; Chatta, G.; Gueron, G.; McNally, L.; Ohm, J.; Wang, J.; Woloszynska, A.
Filiación:Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
Department of Cell Biology, Jagiellonian University, Krakow, 31-007, Poland
Department of Bioinformatics and BioStatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
Child Jesus Hospital, Warsaw, 02-005, Poland
Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
Department of Medicine-GU Center, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
Department of Biological Chemistry, University of Buenos Aires, IQUIBICEN-CONICET, Intendente Guiraldes 2160, CABA, Buenos Aires, 1428, Argentina
Department of Cancer Biology, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC 27157, United States
Department of Cancer Genetics and Genomics, Comprehensive Cancer Center, Buffalo, NY 14263, United States
Título revista:Cell Death and Differentiation
Título revista abreviado:Cell Death Differ.


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---------- APA ----------
Ramakrishnan, S., Granger, V., Rak, M., Hu, Q., Attwood, K., Aquila, L., Krishnan, N.,..., Woloszynska, A. (2019) . Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer. Cell Death and Differentiation.
---------- CHICAGO ----------
Ramakrishnan, S., Granger, V., Rak, M., Hu, Q., Attwood, K., Aquila, L., et al. "Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer" . Cell Death and Differentiation (2019).
---------- MLA ----------
Ramakrishnan, S., Granger, V., Rak, M., Hu, Q., Attwood, K., Aquila, L., et al. "Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer" . Cell Death and Differentiation, 2019.
---------- VANCOUVER ----------
Ramakrishnan, S., Granger, V., Rak, M., Hu, Q., Attwood, K., Aquila, L., et al. Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer. Cell Death Differ. 2019.