SFN Enhanced the Radiosensitivity of Cervical Cancer Cells via Activating LATS2 and Blocking Rad51/MDC1 Recruitment to DNA Damage Site

SIMPLE SUMMARY: Radiotherapy is the main treatment for cervical cancer patients in advanced stages. However a considerable number of patients are not sensitive to radiotherapy. Dysregulation of DNA double-strand break (DSB) repair is characteristic of cancer cells in a radiotherapy-resistance state. The aim of this study is to explore Sulforaphane (SFN) downstream target and the radiotherapy sensitization mechanism in cervical cancer. We identified SFN as cervical cancer cells radiotherapy sensitizer and LATS2 served as a downstream target of SFN treatment. SFN treatment resulted in the inhibition of the homologous recombination (HR) pathway, and LATS2 has an indispensable contribution to this SFN-facilitated radiotherapy sensitization. ABSTRACT: Background: Sulforaphane (SFN) is one kind of phytochemical anticancer drug. It inhibits cancer cell proliferation and promotes cell apoptosis while the mechanism behind is still uncertain. We aimed to explore its downstream target and the radiotherapy sensitization mechanism in cervical cancer. Methods: We treated established cervical cancer cells line (SiHa, HeLa, C33A) with SFN followed by irradiation, and explored its survival, apoptosis, and DNA damage repair in vitro and validated the radiosensitivity of SFN treatment in vivo. We conducted mRNA sequencing to identify differentially expressed mRNAs after SFN treatment. We further investigated SFN downstream target and its involvement in DNA damage repair under irradiation. Results: We found that SFN inhibited the survival of cervical cancer cells under radiotherapy treatment in vitro and prolonged the survival period after radiotherapy in the mouse tumorigenic model. SFN increased the protein expression of LATS2 and promoted apoptosis of cervical cancer cells. Overexpressed LATS2 decreased the cellular survival rate of cervical cancer cells. Additionally, SFN treatment and LATS2 overexpression prevented MDC1 and Rad51 from accumulating in the nucleus in cervical cancer cells after being exposed to ionized radiation. LATS2 loss intervened with SFN-alleviated RAD51 and MDC1 nucleus accumulation and resumed the repairment of DNA damage. Conclusion: We identified SFN as cervical cancer cells radiotherapy sensitizer and LATS2 served as a downstream target of SFN treatment. SFN treatment resulted in the inhibition of the homologous recombination (HR) pathway, and LATS2 has an indispensable contribution to this SFN-facilitated radiotherapy sensitization.