Enhancer RNA promotes resistance to radiotherapy in bone-metastatic prostate cancer by mA modification.

Prostate cancer metastasizes to the bone with the highest frequency and exhibits high resistance to Lu-prostate-specific membrane antigen (PSMA) radioligand therapy. Little is known about bone metastatic prostate cancer (mPCa) resistance to radiation. We filtered the metastatic eRNA using RNA-seq, MeRIP-seq, RT-qPCR and bioinformation. Western blot, RT-qPCR, CLIP, co-IP and RNA pull-down assays were used for RNA/protein interaction, RNA or protein expression examination. MTS assay was used to determine cell viability in vitro, xenograft assay was used to examine the tumor growth in mice. In this study, we screened and identified bone-specific N6 adenosine methylation (mA) on enhancer RNA (eRNA) that played a post-transcriptional functional role in bone mPCa and was correlated with radiotherapy (RT) resistance. Further data demonstrated that RNA-binding protein KHSRP recognized both mA at eRNA and mAm at 5'-UTR of mRNA to block RNA degradation from exoribonuclease XRN2. Depletion of the /KHSRP/ regulatory complex inhibited tumor growth and RT sensitization of bone mPCa xenograft and . Our findings indicate that a bone-specific mA-modified eRNA plays a vital role in regulating mPCa progression and RT resistance and might be a novel specific predictor for cancer RT.