WDR11-DT enhances radiosensitivity via promoting PARP1 degradation and homologous recombination deficiency

Abstract

Radiotherapy is an important management for non-small cell lung cancer (NSCLC). Although long non-coding RNAs (lncRNAs) have been reported to be involved in modulating radiosensitivity, the underlying mechanisms are still largely unclear. Here, we found that tumor suppressor WDR11-DT is a novel radiation-induced lncRNA, which is transcriptionally regulated by SPDEF, in NSCLC. In contrast to normal tissues, WDR11-DT is down-regulated in NSCLC specimens and its low expression was associated with poor prognosis of patient receiving radiotherapy. Importantly, WDR11-DT can markedly enhance NSCLC cells’ radiosensitivity in vitro and in vivo. WDR11-DT functions through distinct mechanisms via binding different proteins. WDR11-DT facilitates interactions between PARP1 and its E3 ligase TRIP12, promotes PARP1 protein degradation and suppresses PARP1-controlled Single-strand breaks (SSBs) repair. Additionally, WDR11-DT binds RNA-bind protein HNRNPK, represses its functions in improving RNA stability of homologous recombination (HR) genes, decreases expression of BRCA1, ATM, BLM and RAD50, and suppresses radiotherapy-triggered HR repair. WDR11-DT-induced dual restraints of PARP1 and the HR pathway lead to the accumulation of double-strand breaks as well as synthetic lethal effects of malignant cells, which, thereby, enhances radiosensitivity and inhibits progression of lung cancer. These results extend our current knowledge of radio-biology and elucidate that WDR11-DT may be a new target for boosting cancer radiotherapy.