文章：

靶向KDM1B依赖性miR-215-AR-AGR2-axis可促进对恩杂鲁胺耐药前列腺癌的敏感性

Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer 

原文发布日期：2021-04-14 

英文摘要：

Post-translational modifications of histones by histone demethylases plays an important role in the regulation of gene transcription and are implicated in cancers. Castrate resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. However, the role of KDM1B involved in next generation anti-enzalutamide resistance and the mechanisms of KDM1B regulation are poorly defined. Here, we show that KDM1B is upregulated and correlated with prostate cancer progression and poor prognosis. Downregulation of miR-215 is correlated with overexpression of KDM1B in enzalutamide-resistant prostate cancer cells, which promotes AR-dependent AGR2 transcription and regulates the sensitivity to next generation AR-targeted therapy. Inhibition of KDM1B significantly inhibits prostate tumor growth and improves enzalutamide treatments through AGR2 suppression. Our studies demonstrate inhibition of KDM1B can offer a viable therapeutic option to overcome enzalutamide resistance in tumors with deregulated miR-215-KDM1B-AR-AGR2 signaling axis. 

摘要翻译：

组蛋白去甲基化酶介导的组蛋白翻译后修饰在基因转录调控中发挥重要作用，且与癌症发生密切相关。去势抵抗性前列腺癌（CRPC）通常由持续活化的雄激素受体驱动，并因此对恩杂鲁胺等现有激素治疗策略产生耐药性。然而，KDM1B在新型抗恩杂鲁胺耐药中的作用及其调控机制尚不明确。本研究表明，KDM1B表达上调与前列腺癌进展及不良预后相关。在恩杂鲁胺耐药前列腺癌细胞中，miR-215的下调与KDM1B过表达存在关联，这种调控关系会促进AR依赖性AGR2转录，并影响对新一代AR靶向治疗的敏感性。抑制KDM1B可通过抑制AGR2显著抑制前列腺肿瘤生长，并增强恩杂鲁胺疗效。我们的研究证实，对于存在miR-215-KDM1B-AR-AGR2信号轴失调的肿瘤，抑制KDM1B可成为克服恩杂鲁胺耐药的有效治疗策略。

原文链接：

Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer