Histone Demethylase KDM4C Stimulates the Proliferation of Prostate Cancer Cells via Activation of AKT and c-Myc
Histone Demethylase KDM4C Stimulates the Proliferation of Prostate Cancer Cells via Activation of AKT and c-Myc
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组蛋白去甲基化酶KDM4C通过激活AKT和c - Myc刺激前列腺癌细胞的增殖
DOI：
10.3390/cancers11111785
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发表时间：
2019-11-01
期刊：
影响因子：
5.2
通讯作者：
Chuu, Chih-Pin
中科院分区：
文献类型：
--
作者：
Lin, Ching-Yu;Wang, Bi-Juan;Chuu, Chih-Pin
我们的三维器官型培养显示，人类组蛋白脱甲基酶（KDM）4C，组蛋白赖氨酸脱甲基酶，阻碍了腺泡形态发生的RWPE-1前列腺细胞，这表明其潜在的致癌作用。KDM 4C的敲低（KD）抑制PCa细胞中的细胞增殖、软琼脂集落形成和雄激素受体（AR）转录活性，以及在斑马鱼异种移植测定中减少人PCa细胞的肿瘤生长。Micro-Western阵列（MWA）分析表明，KDM 4C蛋白KD降低了AKT、c-Myc、AR、mTOR、PDK 1、磷酸化PDK 1 S241、KDM 8和参与细胞周期调节的蛋白的磷酸化，而增加了PTEN的表达。荧光显微镜显示KDM 4C与AR和c-Myc共定位于PCa细胞核中。过表达AKT或c-Myc可恢复KDM 4C KD对PCa细胞增殖的抑制作用。与上述发现相呼应，与邻近的正常前列腺组织相比，KDM 4C的mRNA和蛋白表达在人前列腺肿瘤组织中更高，并且前列腺肿瘤中更高的KDM 4C蛋白表达与更高的AKT和c-Myc蛋白表达水平相关。总之，KDM 4C通过激活c-Myc和AKT促进PCa细胞的增殖。
Our three-dimensional organotypic culture revealed that human histone demethylase (KDM) 4C, a histone lysine demethylase, hindered the acini morphogenesis of RWPE-1 prostate cells, suggesting its potential oncogenic role. Knockdown (KD) of KDM4C suppressed cell proliferation, soft agar colony formation, and androgen receptor (AR) transcriptional activity in PCa cells as well as reduced tumor growth of human PCa cells in zebrafish xenotransplantation assay. Micro-Western array (MWA) analysis indicated that KD of KDM4C protein decreased the phosphorylation of AKT, c-Myc, AR, mTOR, PDK1, phospho-PDK1 S241, KDM8, and proteins involved in cell cycle regulators, while it increased the expression of PTEN. Fluorescent microscopy revealed that KDM4C co-localized with AR and c-Myc in the nuclei of PCa cells. Overexpression of either AKT or c-Myc rescued the suppressive effect of KDM4C KD on PCa cell proliferation. Echoing the above findings, the mRNA and protein expression of KDM4C was higher in human prostate tumor tissues as compared to adjacent normal prostate tissues, and higher KDM4C protein expression in prostate tumors correlated to higher protein expression level of AKT and c-Myc. In conclusion, KDM4C promotes the proliferation of PCa cells via activation of c-Myc and AKT.