Abstract:
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.
Registro:
Documento: |
Artículo
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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
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Año: | 2019
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DOI: |
http://dx.doi.org/10.1038/s41418-019-0278-9 |
Título revista: | Cell Death and Differentiation
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Título revista abreviado: | Cell Death Differ.
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ISSN: | 13509047
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CODEN: | CDDIE
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Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13509047_v_n_p_Ramakrishnan |
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Citas:
---------- 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.
http://dx.doi.org/10.1038/s41418-019-0278-9---------- 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).
http://dx.doi.org/10.1038/s41418-019-0278-9---------- 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.
http://dx.doi.org/10.1038/s41418-019-0278-9---------- 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.
http://dx.doi.org/10.1038/s41418-019-0278-9