KDM2B promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma
KDM2B promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma
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DOI：
10.1016/j.jgg.2021.02.005
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发表时间：
2021-07-20
影响因子：
5.9
通讯作者：
Kimura, Takashi
中科院分区：
文献类型：
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作者：
Gulay, Kevin Christian Montecillo;Aoshima, Keisuke;Kimura, Takashi
表观遗传调节因子与许多类型癌症的肿瘤发生有关；然而，它们在内皮细胞癌如犬血管肉瘤（HSA）中的作用尚未被研究。在这项研究中，我们发现与正常犬内皮细胞相比，赖氨酸特异性去甲基化酶2b （KDM2B）在HSA细胞系中高表达。KDM2B在HSA细胞中的沉默，通过DNA修复通路失活和DNA损伤积累诱导细胞凋亡，导致体外细胞死亡比scramble控制增加。同样，与对照组相比，多西环素诱导的KDM2B沉默在肿瘤异种移植物中导致肿瘤大小减小。此外，KDM2B在HSA的临床病例中也有高表达。我们假设药理学抑制KDM2B也可以诱导HSA细胞死亡，并可作为HSA的替代治疗方法。我们用组蛋白去甲基化酶抑制剂GSK-J4处理HSA细胞，发现GSK-J4处理也能诱导细胞凋亡和细胞死亡。此外，GSK-J4治疗可减小肿瘤大小。因此，我们证明了KDM2B通过增强DNA损伤反应在HSA中起致癌基因的作用。此外，我们发现组蛋白去甲基化酶抑制剂GSK-J4可以作为阿霉素治疗HSA的替代疗法。中国科学院遗传与发育生物学研究所，中国遗传学会版权所有2021爱思唯尔有限公司和科学出版社出版。版权所有。
Epigenetic regulators have been implicated in tumorigenesis of many types of cancer; however, their roles in endothelial cell cancers such as canine hemangiosarcoma (HSA) have not been studied. In this study, we find that lysine-specific demethylase 2b (KDM2B) is highly expressed in HSA cell lines compared with normal canine endothelial cells. Silencing of KDM2B in HSA cells results in increased cell death in vitro compared with the scramble control by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage. Similarly, doxycycline-induced KDM2B silencing in tumor xenografts results in decreased tumor sizes compared with the control. Furthermore, KDM2B is also highly expressed in clinical cases of HSA. We hypothesize that pharmacological KDM2B inhibition can also induce HSA cell death and can be used as an alternative treatment for HSA. We treat HSA cells with GSK-J4, a histone demethylase inhibitor, and find that GSK-J4 treatment also induces apoptosis and cell death. In addition, GSK-J4 treatment decreases tumor size. Therefore, we demonstrate that KDM2B acts as an oncogene in HSA by enhancing the DNA damage response. Moreover, we show that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment. Copyright (C) 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.