The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance. Significance: These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.

中文翻译：

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靶向 KDM6A 抑制 SREBP1c 依赖性脂质代谢和前列腺肿瘤发生

组蛋白去甲基化酶 KDM6A 通过 H3K27 甲基化的表观遗传调控来控制基因表达，并在包括分化、发育和癌症在内的不同过程中发挥作用。在这里，我们研究了 KDM6A 在前列腺癌中的作用。成年小鼠前列腺上皮细胞中 KDM6A 的特异性缺失强烈抑制了由 PTEN 缺失引发的肿瘤进展。从机制上讲，KDM6A 通过与 SREBP1c 启动子结合以增加 SREBP1c 转录来促进前列腺肿瘤发生和脂质代谢。USP7 去泛素化 KDM6A 以增加其表达。KDM6A 在前列腺癌中显着上调，并与 USP7 表达呈正相关。此外，通过在条件性敲除小鼠和异种移植模型中抑制 USP7 来靶向 KDM6A 稳定性显着抑制前列腺癌的生长并显着增强 KDM6A 抑制剂的功效。总的来说，这些发现表明 KDM6A 调节前列腺脂质代谢，并且对于 PTEN 缺失引发的前列腺肿瘤发生至关重要。靶向 USP7/KDM6A 可能是改善前列腺癌进展和治疗耐药性的一种有价值的策略。意义：这些研究结果表明，KDM6A 通过促进 SREBP1c 介导的脂质代谢来支持前列腺肿瘤的发生，建议靶向 USP7/KDM6A 轴作为治疗前列腺癌的治疗策略。这些发现表明 KDM6A 调节前列腺脂质代谢，并且对于 PTEN 缺失引发的前列腺肿瘤发生至关重要。靶向 USP7/KDM6A 可能是改善前列腺癌进展和治疗耐药性的一种有价值的策略。意义：这些研究结果表明，KDM6A 通过促进 SREBP1c 介导的脂质代谢来支持前列腺肿瘤的发生，建议靶向 USP7/KDM6A 轴作为治疗前列腺癌的治疗策略。这些发现表明 KDM6A 调节前列腺脂质代谢，并且对于 PTEN 缺失引发的前列腺肿瘤发生至关重要。靶向 USP7/KDM6A 可能是改善前列腺癌进展和治疗耐药性的一种有价值的策略。意义：这些研究结果表明，KDM6A 通过促进 SREBP1c 介导的脂质代谢来支持前列腺肿瘤的发生，建议靶向 USP7/KDM6A 轴作为治疗前列腺癌的治疗策略。