KDM2B promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma

Kevin Christian Montecillo Gulay; Keisuke Aoshima; Yuki Shibata; Hironobu Yasui; Qin Yan; Atsushi Kobayashi; Takashi Kimura

doi:10.1016/j.jgg.2021.02.005

Volume 48 Issue 7

Jul. 2021

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Article Navigation > Journal of Genetics and Genomics > 2021 > 48(7): 618-630

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KDM2B promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma

doi: 10.1016/j.jgg.2021.02.005

a Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818 Japan;
b Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818 Japan;
c Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA

Funds:

The authors are grateful to Dr. Osamu Ichii, Dr. Junpei Yamazaki, and Dr. Noboru Sasaki for their invaluable support during the conduct of the study. The authors appreciate useful discussions with the members of the Laboratory of Comparative Pathology, Faculty of Veterinary Medicine, Hokkaido University, and the members of Yan laboratory, Department of Pathology, Yale School of Medicine. This research was supported by the Sasakawa Scientific Research Grant (KG, Research No. 2019-4111) provided by the Japan Science Society and the KAKENHI Grant-in-Aid for Young Scientist (KA, Number 18K14575 and 20K15654) provided by Japan Society for the Promotion of Science.

Received Date: 2021-01-30
Accepted Date: 2021-02-28
Rev Recd Date: 2021-02-16
Publish Date: 2021-07-20

Abstract

Abstract

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.
- DNA repair,
- Epigenetics,
- Hemangiosarcoma,
- KDM2B,
- Oncogene

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References(49)

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