Heidari Horestani Mehdi, Atri Roozbahani Golnaz, Baniahmad Aria
Institute of Human Genetics, Jena University Hospital, 07747 Jena, Germany.
Cancers (Basel). 2025 Feb 25;17(5):791. doi: 10.3390/cancers17050791.
Prostate cancer (PCa) is a significant public health issue, particularly in developed countries. The androgen receptor (AR) plays a key role in regulating both the normal development and the proliferation of PCa. Bipolar androgen therapy, which involves treatment with supraphysiological androgen levels (SALs), has been shown to inhibit PCa growth. SAL induces cellular senescence in AR-positive PCa cell lines, human tumor samples, and xenografted mouse models. Transcriptome and chromatin immunoprecipitation (ChIP)-seq analysis, ChIP-qPCR, knockdown (KD), overexpression (OE), qRT-PCR, immunodetection, in situ histochemistry. Here, we show using ChIP-seq and RNA-seq that , a variant of the canonical histone H2A, is a direct target gene of AR that regulates cellular senescence and the formation of senescence-associated heterochromatin foci (SAHF). Accordingly, bioinformatic analyses reveal a large overlap of the H2AJ transcriptome with the cellular senescence score of PCa. Analyzing a large cohort of patient samples, the expression of is higher in tumor samples compared to normal samples suggesting growth-promoting activity. Interestingly, however, the expression is diminished in metastatic tumor samples, indicating that H2AJ inhibits the mesenchymal transition in PCa cells. Functionally, the KD of inhibits growth, whereas the overexpression promotes cell growth. Furthermore, these data suggest that H2AJ inhibits the expression of mesenchymal markers, in agreement with the low expression of in metastatic forms of tumors from patient cohorts. is a direct positively AR-regulated target gene induced by SALs that regulates cellular senescence, promotes growth, and inhibits the expression of mesenchymal markers.
前列腺癌（PCa）是一个重大的公共卫生问题，在发达国家尤为如此。雄激素受体（AR）在调节前列腺癌的正常发育和增殖中起着关键作用。双相雄激素疗法，即使用超生理雄激素水平（SALs）进行治疗，已被证明可抑制前列腺癌生长。SAL可诱导AR阳性前列腺癌细胞系、人肿瘤样本和异种移植小鼠模型中的细胞衰老。转录组和染色质免疫沉淀（ChIP）-seq分析、ChIP-qPCR、敲低（KD）、过表达（OE）、qRT-PCR、免疫检测、原位组织化学。在这里，我们使用ChIP-seq和RNA-seq表明，典型组蛋白H2A的一种变体，是AR的直接靶基因，可调节细胞衰老和衰老相关异染色质灶（SAHF）的形成。因此，生物信息学分析揭示了H2AJ转录组与前列腺癌的细胞衰老评分有很大重叠。分析大量患者样本队列，与正常样本相比，肿瘤样本中H2AJ的表达更高，表明其具有促进生长的活性。然而，有趣的是，在转移性肿瘤样本中其表达降低，这表明H2AJ抑制前列腺癌细胞的间充质转化。在功能上，H2AJ的敲低抑制生长，而过表达则促进细胞生长。此外，这些数据表明H2AJ抑制间充质标志物的表达，这与患者队列中转移性肿瘤形式中H2AJ的低表达一致。H2AJ是一种由SALs诱导的直接受AR正向调控的靶基因，可调节细胞衰老、促进生长并抑制间充质标志物的表达。
