Radiation therapy is a generally utilized treatment modality for malignancies, but many tumor types exhibit significant radioresistance. Epigenetic modifications, including histone methylation, are involved in many physiological processes such as DNA repair by regulating gene transcription. Consequently, combining inhibition of specific histone methyltransferases with radiotherapy may increase radiosensitivity of tumor with significant therapeutic resistance particularly. The methyltransferase of SET8, uniquely specific monomethylated histone H4 lysine 20 (H4K20me1), is involved in several cellular life processes such as transcriptional regulation, cell cycle, DNA repair, genome integrity and tumor metastasis, and is an emerging target for cancer therapy. We found that SET8 and H4K20me1 levels responded to X rays and carbon ions. Inhibition of SET8 was effective to increase radiosensitivity in A549 and MCF7 cells. Furthermore, SET8/H4K20me1 deficiency blocked the kinetics process of DNA damage repair via 53BP1 and γ-H2AX foci reducing. In addition, analyses from clinical data revealed SET8 low expression predicts significantly better response to radiotherapy in LUAD and BRCA patients. Meanwhile, the clinical data analyses also showed that CDC25A, FANCA, MCM7 and POLE, which are DNA repair and proliferation associated genes, had strong positive correlations with SET8 both in LUAD and BRCA patients, suggesting that they may play a key role in SET8 deficiency induced radiosensitivity. In addition, SET8 knockout also significantly inhibited radiation-induced invasion/metastasis capacity of lung adenocarcinoma cells. In conclusion, these results imply that combining inhibition of SET8 which is critical for DNA repair may provide a new therapeutic route for sensitizing tumors to radiotherapy.

Burong Hu got his PhD degree in Biophysics from the University of Chinese Academy of Sciences in 2005 and then started post doctoral work at Coulumbia University (2005.10-2009.02) and UT Southwestern Medical Cente at Dallas (2009.03-2010.02). He worked at the Institute of Modern Physics, Chinese Academy of Sciences (2010.03-2020.08) and Wenzhou Medical University (2020.09-). He is the director of Department of Radiation Medicine and Radiological Health of Wenzhou Medical University. His major is radiobiology and research Interests include: 1) Epigenetic modulation and ionizing irradiation response; 2) Radiation and carcinogenesis. He has over 60 publications.