Silencing UHRF1 Enhances Radiosensitivity of Esophageal Squamous Cell Carcinoma by Inhibiting the PI3K/Akt/mTOR Signaling Pathway

PURPOSE: Resistance to radiotherapy results in a high treatment failure rate for locally advanced esophageal squamous cell carcinoma (ESCC). Ubiquitin-like with plant homeodomain and ring-finger domains 1 (UHRF1), is associated with poor prognosis in ESCC. The present study aims to characterize the effect of UHRF1 silencing on the radiosensitivity of ESCC and its potential mechanism. METHODS: Both in vitro and in vivo experiments were conducted to observe the effects of UHRF1 silencing on the radiosensitivity of ESCC. The effects of UHRF1 silencing on the apoptosis of ESCC cells were assessed by flow cytometry. The expression of apoptosis-related factors (caspase-3 and Bcl-2), PI3K/Akt/mTOR signaling pathway-related factors (PTEN, p-Akt and Akt, p-mTOR and mTOR), and DNMT1 were measured via Western blot, and the status of PTEN methylation was detected by methylation-specific PCR. Immunohistochemistry was used to detect the expressions of PTEN, p-AKT, and p-mTOR in xenograft tumor tissues. RESULTS: In vitro and in vivo experiments showed that UHRF1 knock-down inhibited ESCC cell growth and enhanced their radiosensitivity. shUHRF1 combined with radiation significantly increased ESCC cell apoptosis. Meanwhile, it activated the expression of caspase-3 and inhibited the expression of Bcl-2. shUHRF1 inhibited the expression of DNMT1 and reduced the methylation of PTEN, and then upregulated the expression of PTEN to inhibit the PI3K/Akt/mTOR signaling pathway. On the contrary, the PI3K/Akt/mTOR signaling pathway can be activated by upregulation of UHRF1. CONCLUSION: Our findings provide a theoretical basis for UHRF1 as a target to improve the radiosensitivity of ESCC.