Abstract
Purpose: To determine the effect of Deltex E3 Ubiquitin Ligase 3L (DTX3L) on the radioresistance of prostate cancer (PCa).Methods: A PCa cell model of radioresistance was established via exposure of cancer cell lines to fractionated radiation. The MTT {(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)} assay and western blotting were performed to evaluate the impact of DTX3L on cell survival and DNA damage repair. The molecular mechanism of action was evaluated by western blotting.Results: DTX3L was elevated in PCa cell lines compared with normal primary prostate epithelial cells (p < 0.01). The survival of PCa cells exposed to radiation was promoted by overexpression of DTX3L, while knockdown of DTX3L abrogated the radioresistance. Moreover, overexpression of DTX3Ldecreased phosphorylation of histone H2AX (γH2AX) and increased Rad51 levels (p < 0.01). However, knockdown of DTX3L reversed the accumulation of γH2AX and Rad51. Phosphorylation of AKT was promoted by DTX3L overexpression, but was reduced by DTX3L knockdown (p < 0.01). Inhibition of AKT (protein kinase B) counteracted the promotion ability of DTX3L on the radioresistance of PCa cells via decreased cell survival ratio, and also inhibited DNA damage repair via accumulation of γ-H2AX and depletion of Rad51 (p < 0.01).Conclusion: DTX3L increases the resistance of prostate cancer to radiotherapy and DNA damage repair in PCa via AKT pathway, indicating a potential therapeutic strategy to overcome radioresistance in PCa.
 Keywords: DTX3L (Deltex E3 Ubiquitin Ligase 3L), DNA damage, Phosphorylation, Radioresistance, AKT, Protein kinase B, Prostate cancer
Highlights
Prostate cancer (PCa) is common in males, with an increasing number of cases being diagnosed in the past decade [1]
Deltex E3 Ubiquitin Ligase 3L (DTX3L) can bind with B invasive lymphoma 1, which is important for DLCBL [4]
The present study showed that DTX3L promoted DNA damage repair in radioresistant PCa cells with decreased γH2AX and increased Rad51 levels
Summary
Prostate cancer (PCa) is common in males, with an increasing number of cases being diagnosed in the past decade [1]. AKT (protein kinase B) has been implicated in the mediation of pathways involved in cell proliferation, survival, and metabolism [7]. Activation of AKT via its regulator, phosphoinositide 3-kinase (PI3K), has shown oncogenic ability in various tumors, such as the promotion of metastasis in PCa [7]. Inhibition of AKT has been widely used for the treatment of PCa [8], and PI3K/AKT activation could result in the development of resistance to chemotherapy [9] and radiotherapy [10]. The effect of DTX3L on the AKT pathway involved in the radioresistance of PCa was evaluated. The results could facilitate the development of a potent therapeutic target to overcome radioresistance of PCa. negative control (vector), and DU145 cells were transfected with shRNAs (20 nM) or the negative control (shNC) using Lipofectamine 2000 (Invitrogen). A value of *p < 0.05 or **p < 0.01 was considered statistically significant
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