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Article

Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis

by
Annika Sprüssel
1,2,
Takayoshi Suzuki
3,4,
Naoki Miyata
5,
Kathy Astrahantseff
1,
Annabell Szymansky
1,
Joern Toedling
1,
Theresa M. Thole-Kliesch
1,
Annika Ballagee
1,
Marco Lodrini
1,2,
Annette Künkele
1,2,6,
Matthias Truss
1,
Lukas C. Heukamp
7,
Susanne Mathia
8,9,
Falk Hertwig
1,
Christian Rosenberger
9,
Angelika Eggert
1,2,6,
Hedwig E. Deubzer
1,2,6,10,11 and
Johannes H. Schulte
1,2,6,12,*
1
Department of Pediatric Oncology and Hematology, Charité—Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
2
German Cancer Consortium (DKTK), Partner Sites Berlin and Tuebingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3
SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki 567-0047, Osaka, Japan
4
CREST, Japan Science and Technology Agency (JST), Honcho 4-1-8, Kawaguchi 332-0012, Saitama, Japan
5
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Aichi, Japan
6
Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany
7
Hematopathology Hamburg, Fangdieckstraße 75A, 22547 Hamburg, Germany
8
Department of Vegetative Physiology, Charité—Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
9
Department of Nephrology, Charité—University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany
10
Experimental and Clinical Research Center (ECRC) of Charité and Max-Delbrück-Center of Molecular Medicine in the Helmholtz Association, Lindenberger Weg 80, 13125 Berlin, Germany
11
Max-Delbrück Center of Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125 Berlin, Germany
12
Department of Pediatric Hematology and Oncology, University of Tuebingen, Hoppe-Seyler-Straße 1, 72076 Tuebingen, Germany
 
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*
Author to whom correspondence should be addressed.
J. Clin. Med. 2024, 13(20), 6081; https://doi.org/10.3390/jcm13206081
Submission received: 11 August 2024 / Revised: 27 September 2024 / Accepted: 10 October 2024 / Published: 12 October 2024
(This article belongs to the Special Issue High-Risk Neuroblastoma: New Clinical Insights and Challenges)
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Abstract

Background: The KDM1A histone demethylase regulates the cellular balance between proliferation and differentiation, and is often deregulated in human cancers including the childhood tumor neuroblastoma. We previously showed that KDM1A is strongly expressed in undifferentiated neuroblastomas and correlates with poor patient prognosis, suggesting a possible clinical benefit from targeting KDM1A. Methods: Here, we tested the efficacy of NCL-1, a small molecule specifically inhibiting KDM1A in preclinical models for neuroblastoma. Results: NCL-1 mimicked the effects of siRNA-mediated KDM1A knockdown and effectively inhibited KDM1A activity in four neuroblastoma cell lines and a patient-representative cell model. KDM1A inhibition shifted the aggressive tumor cell phenotypes towards less aggressive phenotypes. The proliferation and cell viability was reduced, accompanied by the induction of markers of neuronal differentiation. Interventional NCL-1 treatment of nude mice harboring established neuroblastoma xenograft tumors reduced tumor growth and inhibited cell proliferation. Reduced vessel density and defects in blood vessel construction also resulted, and NCL-1 inhibited the growth and tube formation of HUVEC-C cells in vitro. Conclusions: Inhibiting KDM1A could attack aggressive neuroblastomas two-fold, by re-directing tumor cells toward a less aggressive, slower-growing phenotype and by preventing or reducing the vascular support of large tumors.
Keywords: epigenetics; histone demethylase; LSD1; targeted therapy; pediatric cancer epigenetics; histone demethylase; LSD1; targeted therapy; pediatric cancer
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MDPI and ACS Style

Sprüssel, A.; Suzuki, T.; Miyata, N.; Astrahantseff, K.; Szymansky, A.; Toedling, J.; Thole-Kliesch, T.M.; Ballagee, A.; Lodrini, M.; Künkele, A.; et al. Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis. J. Clin. Med. 2024, 13, 6081. https://doi.org/10.3390/jcm13206081

AMA Style

Sprüssel A, Suzuki T, Miyata N, Astrahantseff K, Szymansky A, Toedling J, Thole-Kliesch TM, Ballagee A, Lodrini M, Künkele A, et al. Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis. Journal of Clinical Medicine. 2024; 13(20):6081. https://doi.org/10.3390/jcm13206081

Chicago/Turabian Style

Sprüssel, Annika, Takayoshi Suzuki, Naoki Miyata, Kathy Astrahantseff, Annabell Szymansky, Joern Toedling, Theresa M. Thole-Kliesch, Annika Ballagee, Marco Lodrini, Annette Künkele, and et al. 2024. "Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis" Journal of Clinical Medicine 13, no. 20: 6081. https://doi.org/10.3390/jcm13206081

APA Style

Sprüssel, A., Suzuki, T., Miyata, N., Astrahantseff, K., Szymansky, A., Toedling, J., Thole-Kliesch, T. M., Ballagee, A., Lodrini, M., Künkele, A., Truss, M., Heukamp, L. C., Mathia, S., Hertwig, F., Rosenberger, C., Eggert, A., Deubzer, H. E., & Schulte, J. H. (2024). Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis. Journal of Clinical Medicine, 13(20), 6081. https://doi.org/10.3390/jcm13206081

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