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Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

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 osteosa...

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Detalles Bibliográficos
Autores principales: Zhang, Zhongkai, Ha, Sang Hoon, Moon, Young Jae, Hussein, Usama Khamis, Song, Yiping, Kim, Kyoung Min, Park, See-Hyoung, Park, Ho Sung, Park, Byung-Hyun, Ahn, Ae-Ri, Lee, Sang-A, Ahn, Su Jin, Kim, Jung Ryul, Jang, Kyu Yun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670730/
https://www.ncbi.nlm.nih.gov/pubmed/33198792
http://dx.doi.org/10.1186/s13046-020-01759-9
Descripción
Sumario: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.