Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer.
Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer.
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KDM5B在前列腺发育和前列腺癌中上下文相关功能的证据。
DOI：
10.18632/oncotarget.27818
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发表时间：
2020-11-17
期刊：
影响因子：
--
通讯作者：
Tang DG
中科院分区：
文献类型：
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作者：
Liu B;Kumar R;Chao HP;Mehmood R;Ji Y;Tracz A;Tang DG
前列腺癌（PCa）是全球癌症相关死亡的主要原因之一。前列腺肿瘤发生和 PCa 进展涉及许多遗传和表观遗传扰动。组蛋白修饰代表了调节多种细胞过程的基本表观遗传机制，而 H3K4 甲基化（一种与活性转录相关的组蛋白修饰）可以通过专用组蛋白去甲基化酶 KDM5B (JARID1B) 逆转。 KDM5B 的异常表达和功能与包括 PCa 在内的多种癌症类型有关。我们的生物信息学分析一致表明，与良性前列腺组织相比，PCa 中 KDM5B mRNA 水平上调，并且与肿瘤分级增加和患者生存率低相关，支持 KDM5B 在 PCa 中的致癌功能。然而，令人惊讶的是，当我们使用 Probasin (Pb) 启动子驱动的 Cre:loxP 系统生成前列腺特异性条件 Kdm5b 敲除小鼠时，我们观察到 Kdm5b 缺失并不影响正常前列腺发育，而是诱导轻度增生。这些结果表明，KDM5B 在正常前列腺发育与 PCa 发育和进展中可能具有背景依赖性作用。
Prostate cancer (PCa) is one of the leading causes of cancer-related deaths worldwide. Prostate tumorigenesis and PCa progression involve numerous genetic as well as epigenetic perturbations. Histone modification represents a fundamental epigenetic mechanism that regulates diverse cellular processes, and H3K4 methylation, one such histone modification associated with active transcription, can be reversed by dedicated histone demethylase KDM5B (JARID1B). Abnormal expression and functions of KDM5B have been implicated in several cancer types including PCa. Consistently, our bioinformatics analysis reveals that the KDM5B mRNA levels are upregulated in PCa compared to benign prostate tissues, and correlate with increased tumor grade and poor patient survival, supporting an oncogenic function of KDM5B in PCa. Surprisingly, however, when we generated prostate-specific conditional Kdm5b knockout mice using probasin (Pb) promoter-driven Cre: loxP system, we observed that Kdm5b deletion did not affect normal prostate development but instead induced mild hyperplasia. These results suggest that KDM5B may possess context-dependent roles in normal prostate development vs. PCa development and progression.