ZNF582 Methylation Predicts Better Radiotherapy Response of Cervical Cancer and ZNF582 Overexpression Reduces Radiosensitivity by Arresting the Cell Cycle in S Phase

Abstract Purpose: Our previous studies identified ZNF582 methylation (ZNF582m) level as a useful biomarker for cervical cancer screening, detection, and prognosis. The purpose of this study is to investigate the relationship between ZNF582m level and cervical cancer radiotherapy sensitivity and its underlying mechanism.Patients and Methods: This was a prospective multicenter clinical study, included two independent cohorts locally advanced cervical cancer patients. Exfoliated cervical cancer cells were collected pre-treatment and during treatment (after 24, 30, 36, 48, and 64 Gy) to test ZNF582m level, radiotherapy response evaluated according to RECIST Version. Results: In the first cohort, 22 cases achieved satisfied response, 28 exhibited modest response. Radiotherapy reduced ZNF582m level among all patients. Baseline ZNF582m was significantly higher in the satisfied response cases than in modest response cases, also, patients with high baseline ZNF582m (ZNF582m-high, n = 21) were more sensitive to radiotherapy than ZNF582m-low patients (n = 29), as evidenced by greater satisfied response rate (76.2% vs. 20.7%). An independent cohort confirmed above results. The magnitude of ZNF582m reduction was associated with a radiotherapeutic response, a subset of ZNF582m-low patients (5 of 28) exhibiting a transient increase in ZNF582m demonstrated greater radiosensitivity than other ZNF582m-low patients. ZNF582 overexpression induced cell cycle arrest in S phase.Conclusion: High ZNF582m level predicts better cervical cancer radiosensitivity, ZNF582 overexpression reduces radiosensitivity by cell cycle arrest.