Objective SET8 is a member of the SET domain-containing family and the only known lysine methyltransferase (KMT) that monomethylates lysine 20 of histone H4 (H4K20me1). SET8 has been implicated in many essential cellular processes, including cell cycle regulation, DNA replication, DNA damage response, and carcinogenesis. There is no conclusive evidence, however, regarding the effect of SET8 on radiotherapy. In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tumors and the underlying mechanism. Methods First, we explored the radiotherapy benefit of the SET8 expression signature by analyzing clinical data. Then, we measured a series of biological endpoints, including the xenograft tumor growth in mice and apoptosis, frequency of micronuclei, and foci of 53BP1 and γ-H2AX in cells to detect the SET8 effects on radiosensitivity. RNA sequencing and subsequent experiments were exploited to verify the mechanism underlying the SET8 effects on radiotherapy. Results Low expression of SET8 predicted a better benefit to radiotherapy in lung adenocarcinoma (LUAD) and invasive breast carcinoma (BRCA) patients. Furthermore, genetic deletion of SET8 significantly enhanced radiation treatment efficacy in a murine tumor model, and A549 and MCF7 cells; SET8 overexpression decreased the radiosensitivity. SET8 inhibition induced more apoptosis, the frequency of micronuclei, and blocked the kinetics process of DNA damage repair as 53BP1 and γ-H2AX foci remained in cells. Moreover, RNF8 was positively correlated with the SET8 impact on DNA damage repair. Conclusion Our results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing DNA damage repair, thus suggesting that SET8 potentiated radiotherapy of carcinomas. As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings, combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.

PAN Dong;DU Ya Rong;LI Rong;SHEN Ai Hua;LIU Xiao Dong;LI Chuan Yuan;HU Bu Rong

Department of Radiological Health and Radiation Medicine,School of Public Health and Management,Wenzhou Medical University,Wenzhou 325035,Zhejiang,China;Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences&Key laboratory of Space Radiobiology of Gansu province,Institute of Modern Physics,Chinese Academy of Sciences,Lanzhou 730000,Gansu,China;Department of Dermatology,Duke University Medical Center,Durham,NC,27710,USA

生物医学与环境科学（英文版）

[1]PAN Dong;DU Ya Rong;LI Rong;SHEN Ai Hua;LIU Xiao Dong;LI Chuan Yuan;HU Bu Rong-.SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas)[J].生物医学与环境科学（英文版）,2022(03):194-205,前插5-前插8

Potentiates,Carcinomas,KMT,monomethylates,micronuclei,RNF8

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