SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas.

Dong Pan; Ya Rong DU; Rong LI; Ai Hua Shen; Xiao Dong Liu; Chuan Yuan LI; Bu Rong HU

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SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas.

Author: Dong PAN ^{1
,

2
,

3} ; Ya Rong DU ⁴ ; Rong LI ⁵ ; Ai Hua SHEN ⁵ ; Xiao Dong LIU ⁵ ; Chuan Yuan LI ³ ; Bu Rong HU ^{1
,

4}
Author Information

1. Department of Radiological Health and Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
2. 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
3. Department of Dermatology, Duke University Medical Center, Durham, NC, 27710, USA.
4. 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.
5. Department of Radiological Health and Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
Publication Type:Journal Article
Keywords: Carcinoma; DNA repair; Histone methylation; Radiotherapy; SET8
MeSH: Animals; Apoptosis; Carcinogenesis; Carcinoma/radiotherapy*; Cell Cycle; Cell Line, Tumor; DNA Damage; DNA Replication; HeLa Cells; Histone-Lysine N-Methyltransferase; Humans; Mice; Radiotherapy
From: Biomedical and Environmental Sciences 2022;35(3):194-205
CountryChina
Language:English
Abstract: 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.