Department of Urology, Disorders of Prostate Cancer Multidisciplinary Team, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
Andrology Center, Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
Clin Transl Med. 2024 Jan;14(1):e1531. doi: 10.1002/ctm2.1531.
Prostate cancer (PCa) initially shows satisfactory response to therapies targeting the androgen receptor (AR). However, progression to a castration-resistant stage indicates poor prognosis in PCa patients. AR signalling still plays a central role in most castration-resistant prostate cancers (CRPC). Therefore, unveiling the mechanisms of AR reactivation under androgen-deprived conditions is imperative to discover novel therapeutic targets for CRPC.
Using an integrative analysis of the transcriptomics of three independent PCa cohorts and a published landscape of AR-regulated long non-coding RNA (lncRNA), lncRNA LINC01126 was selected as a candidate gene that could drive CRPC progression for further study. Quantitative reverse transcription polymerase chain reaction, in situ hybridisation (ISH) and fluorescent ISH were performed to detect LINC01126 in PCa tissues and cells. The functional role and mechanism of LINC01126 were further investigated using in vitro and in vivo gain and loss of function assays.
LINC01126, identified as an AR-repressed lncRNA, was significantly upregulated after AR-targeted therapies. In addition, we found that LINC01126 was upregulated in CRPC and was associated with poor prognosis. We also proved that LINC01126 stabilised AR protein and enhanced AR nuclear translocation and transactivation by promoting the transition from O-GlcNAcylation at threonine 80 to phosphorylation at serine 81 (S81) within the AR protein. Mechanism analysis revealed that LINC01126 facilitates the interaction of CDK9 with AR and impedes the binding of O-linked N-acetylglucosamine (O-GlcNAc) transferase to AR. Consequently, LINC01126 expression was sufficient to activate AR signalling without androgen. LINC01126 overexpression increased, whereas LINC01126 knockdown decreased castration resistance traits in PCa cells in vitro and in vivo. Furthermore, our data showed that LINC01126-targeting antisense oligonucleotides (ASO) substantially inhibited CRPC cells in vitro.
Our research expands the functions of AR-regulated lncRNA in sustaining androgen-independent AR activity and promoting CRPC progression and reveals that LINC01126 may be a new therapeutic target for PCa.
前列腺癌 (PCa) 最初对靶向雄激素受体 (AR) 的治疗有满意的反应。然而，进展到去势抵抗阶段表明 PCa 患者预后不良。AR 信号在大多数去势抵抗性前列腺癌 (CRPC) 中仍发挥核心作用。因此，揭示雄激素剥夺条件下 AR 重新激活的机制对于发现 CRPC 的新治疗靶点至关重要。
通过对三个独立的 PCa 队列的转录组学和已发表的 AR 调控长链非编码 RNA (lncRNA) 图谱的综合分析，选择 lncRNA LINC01126 作为候选基因，用于进一步研究其可能驱动 CRPC 进展。使用定量逆转录聚合酶链反应、原位杂交 (ISH) 和荧光 ISH 检测 PCa 组织和细胞中的 LINC01126。使用体外和体内增益和功能丧失测定进一步研究 LINC01126 的功能作用和机制。
LINC01126 作为一种被 AR 抑制的 lncRNA，在 AR 靶向治疗后显著上调。此外，我们发现 LINC01126 在 CRPC 中上调，并与预后不良相关。我们还证明 LINC01126 通过促进 AR 蛋白中苏氨酸 80 位的 O-连接的 N-乙酰葡糖胺 (O-GlcNAc) 化到丝氨酸 81 位的磷酸化 (S81) 的转变，稳定 AR 蛋白并增强 AR 核易位和转录激活。机制分析表明，LINC01126 促进 CDK9 与 AR 的相互作用，并阻碍 O-连接的 N-乙酰葡糖胺 (O-GlcNAc) 转移酶与 AR 的结合。因此，LINC01126 的表达足以在没有雄激素的情况下激活 AR 信号。LINC01126 的过表达增加，而 LINC01126 的敲低减少了体外和体内的 PCa 细胞的去势抵抗特性。此外，我们的数据表明，LINC01126 靶向反义寡核苷酸 (ASO) 可显著抑制体外的 CRPC 细胞。
我们的研究扩展了 AR 调控 lncRNA 在维持雄激素非依赖性 AR 活性和促进 CRPC 进展中的功能，并表明 LINC01126 可能成为 PCa 的新治疗靶点。
