Enhancer RNA promotes resistance to radiotherapy in bone-metastatic prostate cancer by m6A modification

• Published in: Theranostics 2023-01, Vol.13 (2), p.596-610
• Main Authors: Zhao, Yu, Wen, Simeng, Li, Hang, Chun-Wu, Pan, Wei, Yulei, Huang, Ting, Li, Zhaochen, Yang, Yinhui, Fan, Saijun, Zhang, Yingyi
• Format: Article
• Language: English
• Subjects: Androgens; Antibodies; Cancer therapies; CRISPR; Gene expression; Medical prognosis; Metastasis; Mutagenesis; Patients; Prostate cancer; Radiation therapy; Research Paper; RNA polymerase; Transplants & implants; Tumors
• ISSN: 1838-7640
• DOI: 10.7150/thno.78687

Rationale: Prostate cancer metastasizes to the bone with the highest frequency and exhibits high resistance to 177Lu-prostate-specific membrane antigen (PSMA) radioligand therapy. Little is known about bone metastatic prostate cancer (mPCa) resistance to radiation.Methods: 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.Results: In this study, we screened and identified bone-specific N6 adenosine methylation (m6A) 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 m6A at eRNA and m6Am at 5'-UTR of mRNA to block RNA degradation from exoribonuclease XRN2. Depletion of the MLXIPe/KHSRP/PSMD9 regulatory complex inhibited tumor growth and RT sensitization of bone mPCa xenograft in vitro and in vivo.Conclusions: Our findings indicate that a bone-specific m6A-modified eRNA plays a vital role in regulating mPCa progression and RT resistance and might be a novel specific predictor for cancer RT.