Background: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.Methods:Transcriptome and chromatin immunoprecipitation (ChIP)-seq analysis, ChIP-qPCR, knockdown (KD), overexpression (OE), qRT-PCR, immunodetection, in situ histochemistry.Results:Here, we show using ChIP-seq and RNA-seq thatH2AJ, 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 ofH2AJis 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 ofH2AJinhibits growth, whereas theH2AJoverexpression promotes cell growth. Furthermore, these data suggest that H2AJ inhibits the expression of mesenchymal markers, in agreement with the low expression ofH2AJin metastatic forms of tumors from patient cohorts.Conclusion:H2AJis a direct positively AR-regulated target gene induced by SALs that regulates cellular senescence, promotes growth, and inhibits the expression of mesenchymal markers.
背景：前列腺癌（PCa）是一个重要的公共卫生问题，尤其在发达国家。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。双极雄激素疗法，即通过超生理水平雄激素（SALs）进行治疗，已被证明能抑制前列腺癌的生长。SAL可诱导AR阳性前列腺癌细胞系、人类肿瘤样本以及异种移植小鼠模型中的细胞衰老。 方法：采用转录组和染色质免疫沉淀测序（ChIP-seq）分析、ChIP-qPCR、基因敲低（KD）、过表达（OE）、qRT-PCR、免疫检测以及原位组织化学技术。 结果：本研究通过ChIP-seq和RNA-seq分析发现，经典组蛋白H2A的变体H2AJ是AR的直接靶基因，调控细胞衰老及衰老相关异染色质灶（SAHF）的形成。生物信息学分析进一步显示，H2AJ转录组与前列腺癌的细胞衰老评分存在高度重叠。对大量患者样本的分析表明，与正常样本相比，肿瘤样本中H2AJ的表达更高，提示其具有促生长活性。然而有趣的是，转移性肿瘤样本中H2AJ的表达降低，表明H2AJ能抑制前列腺癌细胞的间质转化。在功能上，敲低H2AJ会抑制细胞生长，而过表达H2AJ则促进细胞生长。此外，这些数据表明H2AJ抑制间质标志物的表达，这与患者队列中转移性肿瘤样本中H2AJ的低表达情况一致。 结论：H2AJ是SALs诱导的、受AR直接正向调控的靶基因，它调控细胞衰老、促进细胞生长并抑制间质标志物的表达。
肿瘤(癌症)患者之家