Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer

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...

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Autores principales: 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.
Formato: JOUR
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_13509047_v_n_p_Ramakrishnan
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
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spelling todo:paper_13509047_v_n_p_Ramakrishnan2023-10-03T16:10:05Z Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer 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. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_13509047_v_n_p_Ramakrishnan
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
description 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.
format JOUR
author 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.
spellingShingle 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
author_facet 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.
author_sort Ramakrishnan, S.
title Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer
title_short Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer
title_full Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer
title_fullStr Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer
title_full_unstemmed Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer
title_sort inhibition of ezh2 induces nk cell-mediated differentiation and death in muscle-invasive bladder cancer
url http://hdl.handle.net/20.500.12110/paper_13509047_v_n_p_Ramakrishnan
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