Abstract
Ionizing radiation (IR) can induce DNA double-strand breaks (DSBs) in tumor cells during radiotherapy (RT), but the efficiency of RT is limited because of the toxicity to normal cells. Locating an adjuvant treatment to alleviate damage in normal cells while sensitizing tumor cells to IR has attracted much attention. Here, using the 7,12-dimethylbenz[α]anthracene (DMBA)-induced malignant transformed MCF10A cells, we found that valproate (VPA), a histone deacetylase inhibitor (HDACi), radiosensitized transformed cells while alleviated IR-induced damage in normal cells at a safe dose (0.5 mM). We further demonstrated the decrease of homologous recombination (HR)-associated Rad51 in the transformed cells was related to the increase of its ubiquitination regulated by E3 ligase RFWD3 for the radiosensitization, which was opposite to normal cells, indicating that RFWD3-dependent ubiquitination on Rad51 was involved in the VPA-mediated radio-bidirectional effect. Through DMBA-transformed breast cancer rat model, VPA at 200 mg/kg radiosensitized tumor tissue cells by increasing RFWD3 and inhibited Rad51, while radioprotected normal tissue cells by decreasing RFWD3 and enhanced Rad51. In addition, we found high-level Rad51 was associated with tumorigenesis and poor prognosis in breast cancer patients. Our findings uncovered RFWD3-dependent Rad51 ubiquitination was the novel mechanism of VPA-mediated radio-bidirectional effect, VPA is a potential adjuvant treatment for tumor RT.
Highlights
Radiotherapy (RT) has been proven effective in managing breast cancer and other malignancies [1], but the toxicity and the bystander adverse effect induced by ionizing radiation (IR) have limited the popularity of this oncological treatment modality [2,3,4]
A suitable dose of DMBA treatment on MCF10A cells was explored through MTT assay
Since we discovered that the Rad51 protein stability was related to the VPA-mediated bidirectional effect, it is necessary to detect its ubiquitination in the paired cell line
Summary
Radiotherapy (RT) has been proven effective in managing breast cancer and other malignancies [1], but the toxicity and the bystander adverse effect induced by ionizing radiation (IR) have limited the popularity of this oncological treatment modality [2,3,4]. Locating an efficacious and safe oncological treatment modality is of clinical importance. IR induces intracellular DNA damage, the most lethal DNA double-strand breaks (DSBs), and triggers sophisticated DNA repair pathways, including error-free homologous recombination (HR) and error-prone nonhomologous end-joining (NHEJ) [6]. HR acts as an effective DSBs repair pathway to keep genomic stability [5]. Rad has been identified as the central protein in HR, which forms helical nucleoprotein filaments on tracts of single-strand DNA (ssDNA) at DSBs sites [7]. Rad regulates stalled replication forks by protecting newly synthesized DNA from degradation [8, 9], promoting replication fork regression [9, 10], and reinstates the collapsed replication forks [11]
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