Sprüssel Annika, Suzuki Takayoshi, Miyata Naoki, Astrahantseff Kathy, Szymansky Annabell, Toedling Joern, Thole-Kliesch Theresa M, Ballagee Annika, Lodrini Marco, Künkele Annette, Truss Matthias, Heukamp Lukas C, Mathia Susanne, Hertwig Falk, Rosenberger Christian, Eggert Angelika, Deubzer Hedwig E, Schulte Johannes H
Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
German Cancer Consortium (DKTK), Partner Sites Berlin and Tuebingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
J Clin Med. 2024 Oct 12;13(20):6081. doi: 10.3390/jcm13206081.
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. Here, we tested the efficacy of NCL-1, a small molecule specifically inhibiting KDM1A in preclinical models for neuroblastoma. 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. : 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.
KDM1A组蛋白去甲基化酶调节细胞增殖与分化之间的平衡，在包括儿童肿瘤神经母细胞瘤在内的人类癌症中常发生失调。我们之前表明KDM1A在未分化的神经母细胞瘤中强烈表达，且与患者预后不良相关，提示靶向KDM1A可能具有临床益处。在此，我们在神经母细胞瘤的临床前模型中测试了NCL-1（一种特异性抑制KDM1A的小分子）的疗效。NCL-1模拟了siRNA介导的KDM1A敲低的效果，并有效抑制了四种神经母细胞瘤细胞系和一个患者代表性细胞模型中的KDM1A活性。KDM1A抑制使侵袭性肿瘤细胞表型转变为侵袭性较弱的表型。增殖和细胞活力降低，同时伴有神经元分化标志物的诱导。对携带已建立的神经母细胞瘤异种移植肿瘤的裸鼠进行NCL-1干预治疗可减少肿瘤生长并抑制细胞增殖。还导致血管密度降低和血管构建缺陷，并且NCL-1在体外抑制HUVEC-C细胞的生长和管形成。抑制KDM1A可以通过将肿瘤细胞重定向为侵袭性较弱、生长较慢的表型以及通过预防或减少大肿瘤的血管支持，从两个方面攻击侵袭性神经母细胞瘤。
