The Novel Direct AR Target Gene Annexin A2 Mediates Androgen-Induced Cellular Senescence in Prostate Cancer Cells.

IF 2.1 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Kimia Mirzakhani, Mehdi Heidari Horestani, Julia Kallenbach, Golnaz Atri Roozbahani, Aria Baniahmad
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引用次数: 0

Abstract

Clinical trials for prostate cancer (PCa) patients have implemented the bipolar androgen therapy (BAT) that includes the treatment with supraphysiological androgen level (SAL). SAL treatment induces cellular senescence in tumor samples of PCa patients and in various PCa cell lines, including castration-resistant PCa (CRPC), and is associated with enhanced phospho-AKT levels. Using an AKT inhibitor (AKTi), the SAL-mediated cell senescence is inhibited. Here, we show by RNA-seq analyses of two human PCa cell lines, that annexin A2 (ANXA2) expression is induced by SAL and repressed by co-treatment with AKTi. Higher ANXA2 expression is associated with better survival of PCa patients and suggests that ANXA2 is part of SAL-mediated tumor suppressive activity. ChIP-seq revealed that AR is recruited to the intronic regions of ANXA2 gene suggesting that ANXA2 is a novel direct AR target gene. Knockdown of ANXA2 shows that SAL-induced cellular senescence is mediated by ANXA2 and enhances the levels of phospho-AKT indicating an interaction between the AR, ANXA2 and AKT. Notably, we found that the level of heat shock protein HSP27, known to interact with ANXA2, is associated with cellular senescence. HSP27 level is induced by SAL but the induction is blunted by knockdown of ANXA2 suggesting a novel ANXA2-HSP27 pathway in PCa. This was confirmed using an HSP27 inhibitor that reduced the SAL-induced cellular senescence levels suggesting that ANXA2 upregulates HSP27 to mediate AR-signaling in SAL-induced cellular senescence. Thus, the data indicate ANXA2-HSP27 cross-talk as novel factors in the signaling by the AR-AKT pathway to mediate cellular senescence.

新的直接 AR 靶基因 Annexin A2 在前列腺癌细胞中介导雄激素诱导的细胞衰老。
针对前列腺癌(PCa)患者的临床试验采用了双极雄激素疗法(BAT),其中包括超生理雄激素水平(SAL)治疗。SAL 治疗会诱导 PCa 患者肿瘤样本和各种 PCa 细胞系(包括阉割耐药 PCa (CRPC))中的细胞衰老,并与磷酸化 AKT 水平升高有关。使用 AKT 抑制剂(AKTi)可以抑制 SAL 介导的细胞衰老。在这里,我们通过对两种人类 PCa 细胞系进行 RNA-seq 分析表明,SAL 会诱导附件素 A2(ANXA2)的表达,而与 AKTi 联合处理则会抑制 ANXA2 的表达。较高的 ANXA2 表达与 PCa 患者较好的生存率相关,这表明 ANXA2 是 SAL 介导的肿瘤抑制活性的一部分。ChIP-seq 发现,AR 被招募到了 ANXA2 基因的内含子区域,这表明 ANXA2 是一个新的直接 AR 靶基因。敲除ANXA2表明,SAL诱导的细胞衰老是由ANXA2介导的,并且提高了磷酸AKT的水平,这表明AR、ANXA2和AKT之间存在相互作用。值得注意的是,我们发现已知与 ANXA2 相互作用的热休克蛋白 HSP27 的水平与细胞衰老有关。SAL 会诱导 HSP27 的水平,但 ANXA2 的敲除会减弱这种诱导作用,这表明 PCa 中存在一种新的 ANXA2-HSP27 通路。使用 HSP27 抑制剂可降低 SAL 诱导的细胞衰老水平,从而证实了 ANXA2 上调 HSP27 在 SAL 诱导的细胞衰老中介导 AR 信号。因此,这些数据表明 ANXA2-HSP27 相互交织是 AR-AKT 通路信号转导细胞衰老的新因素。
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来源期刊
Biochemical Genetics
Biochemical Genetics 生物-生化与分子生物学
CiteScore
3.90
自引率
0.00%
发文量
133
审稿时长
4.8 months
期刊介绍: Biochemical Genetics welcomes original manuscripts that address and test clear scientific hypotheses, are directed to a broad scientific audience, and clearly contribute to the advancement of the field through the use of sound sampling or experimental design, reliable analytical methodologies and robust statistical analyses. Although studies focusing on particular regions and target organisms are welcome, it is not the journal’s goal to publish essentially descriptive studies that provide results with narrow applicability, or are based on very small samples or pseudoreplication. Rather, Biochemical Genetics welcomes review articles that go beyond summarizing previous publications and create added value through the systematic analysis and critique of the current state of knowledge or by conducting meta-analyses. Methodological articles are also within the scope of Biological Genetics, particularly when new laboratory techniques or computational approaches are fully described and thoroughly compared with the existing benchmark methods. Biochemical Genetics welcomes articles on the following topics: Genomics; Proteomics; Population genetics; Phylogenetics; Metagenomics; Microbial genetics; Genetics and evolution of wild and cultivated plants; Animal genetics and evolution; Human genetics and evolution; Genetic disorders; Genetic markers of diseases; Gene technology and therapy; Experimental and analytical methods; Statistical and computational methods.
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