Kallenbach Julia, Rasa Mahdi, Heidari Horestani Mehdi, Atri Roozbahani Golnaz, Schindler Katrin, Baniahmad Aria
Institute of Human Genetics, Jena University Hospital, Am Klinikum 1, Jena, 07740, Germany.
Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
J Exp Clin Cancer Res. 2024 Dec 16;43(1):321. doi: 10.1186/s13046-024-03233-2.
The androgen receptor (AR), a ligand-dependent transcription factor, plays a key role in regulating prostate cancer (PCa) growth. The novel bipolar androgen therapy (BAT) uses supraphysiological androgen levels (SAL) that suppresses growth of PCa cells and induces cellular senescence functioning as a tumor suppressive mechanism. The role of long non-coding RNAs (lncRNAs) in the regulation of SAL-mediated senescence remains unclear. This study focuses on the SAL-repressed lncRNA MIR503HG, examining its involvement in androgen-controlled cellular senescence in PCa.
Transcriptome and ChIP-Seq analyses of PCa cells treated with SAL were conducted to identify SAL-downregulated lncRNAs. Expression levels of MIR503HG were analyzed in 691 PCa patient tumor samples, mouse xenograft tumors and treated patient-derived xenografts. Knockdown and overexpression experiments were performed to assess the role of MIR503HG in cellular senescence and proliferation using senescence-associated β-Gal assays, qRT-PCRs, and Western blotting. The activity of MIR503HG was confirmed in PCa tumor spheroids.
A large patient cohort analysis shows that MIR503HG is overexpressed in metastatic PCa and is associated with reduced patient survival, indicating its potential oncogenic role. Notably, SAL treatment suppresses MIR503HG expression across four different PCa cell lines and patient-derived xenografts but interestingly not in the senescence-resistant LNCaP Abl EnzaR cells. Functional assays reveal that MIR503HG promotes PCa cell proliferation and inhibits SAL-mediated cellular senescence, partly through miR-424-5p. Mechanistic analyses and rescue experiments indicate that MIR503HG regulates the AKT-p70S6K and the p15-pRb pathway. Reduced expression of MIR503HG by SAL or knockdown resulted in decreased BRCA2 levels suggesting a role in DNA repair mechanisms and potential implications for PARP inhibitor sensitivity by SAL used in BAT clinical trial.
The lncRNA MIR503HG acts as an oncogenic regulator in PCa by repressing cellular senescence. SAL-induced suppression of MIR503HG enhances the tumor-suppressive effects of AR signaling, suggesting that MIR503HG could serve as a biomarker for BAT responsiveness and as a target for combination therapies with PARP inhibitors.
雄激素受体（AR）是一种依赖配体的转录因子，在调节前列腺癌（PCa）生长中起关键作用。新型双相雄激素疗法（BAT）使用超生理雄激素水平（SAL），其可抑制PCa细胞生长并诱导细胞衰老，发挥肿瘤抑制机制的作用。长链非编码RNA（lncRNA）在SAL介导的衰老调节中的作用尚不清楚。本研究聚焦于SAL抑制的lncRNA MIR503HG，研究其在PCa雄激素控制的细胞衰老中的作用。
对用SAL处理的PCa细胞进行转录组和ChIP-Seq分析，以鉴定SAL下调的lncRNA。在691例PCa患者肿瘤样本、小鼠异种移植瘤和经治疗的患者来源异种移植瘤中分析MIR503HG的表达水平。进行敲低和过表达实验，使用衰老相关β-半乳糖苷酶检测、qRT-PCR和蛋白质印迹法评估MIR503HG在细胞衰老和增殖中的作用。在PCa肿瘤球体中证实了MIR503HG的活性。
一项大型患者队列分析表明，MIR503HG在转移性PCa中过表达，且与患者生存率降低相关，表明其潜在的致癌作用。值得注意的是，SAL处理可抑制四种不同PCa细胞系和患者来源异种移植瘤中MIR503HG的表达，但有趣的是，在对衰老有抗性的LNCaP Abl EnzaR细胞中却没有。功能分析表明，MIR503HG促进PCa细胞增殖并抑制SAL介导的细胞衰老，部分是通过miR-424-5p实现的。机制分析和挽救实验表明，MIR503HG调节AKT-p70S6K和p15-pRb途径。SAL或敲低导致MIR503HG表达降低，从而使BRCA2水平降低，这表明其在DNA修复机制中的作用以及对BAT临床试验中使用的SAL的PARP抑制剂敏感性的潜在影响。
lncRNA MIR503HG通过抑制细胞衰老在PCa中作为致癌调节因子发挥作用。SAL诱导的MIR5HG抑制增强了AR信号通路的肿瘤抑制作用，这表明MIR503HG可作为BAT反应性生物标志物以及与PARP抑制剂联合治疗的靶点。
