Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathwa
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(2020) 39:247
RESEARCH
Open Access
Inhibition of SIRT6 potentiates the antitumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma Zhongkai Zhang1†, Sang Hoon Ha2†, Young Jae Moon3,4, Usama Khamis Hussein4,5,6, Yiping Song1, Kyoung Min Kim4,5, See-Hyoung Park7, Ho Sung Park4,5, Byung-Hyun Park3, Ae-Ri Ahn5, Sang-A Lee5, Su Jin Ahn3, Jung Ryul Kim1,4* and Kyu Yun Jang4,5*
Abstract Background: SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods: We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results: Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions: This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6. Keywords: Osteosarcoma, SIRT6, doxorubicin, apoptosis, DNA damage
* Correspondence: [email protected]; [email protected] † Zhongkai Zhang and Sang Hoon Ha contributed equally to this work. 1 Department of Orthopedic Surgery, Jeonbuk National University Medical School, Jeonju, Republic of Korea 4 Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To vie
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