Myc 通过转录和转录后机制在早期前列腺肿瘤中强制 EZH2 过表达。
Myc enforces overexpression of EZH2 in early prostatic neoplasia via transcriptional and post-transcriptional mechanisms.
作者信息
Koh Cheryl M, Iwata Tsuyoshi, Zheng Qizhi, Bethel Carlise, Yegnasubramanian Srinivasan, De Marzo Angelo M
机构信息
Departments of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
出版信息
Oncotarget. 2011 Sep;2(9):669-83. doi: 10.18632/oncotarget.327.
EZH2 is part of the PRC2 polycomb repressive complex that is overexpressed in multiple cancer types and has been implicated in prostate cancer initiation and progression. Here, we identify EZH2 as a target of the MYC oncogene in prostate cancer and show that MYC coordinately regulates EZH2 through transcriptional and post-transcriptional means. Although prior studies in prostate cancer have revealed a number of possible mechanisms of EZH2 upregulation, these changes cannot account for the overexpression EZH2 in many primary prostate cancers, nor in most cases of high grade PIN. We report that upregulation of Myc in the mouse prostate results in overexpression of EZH2 mRNA and protein which coincides with reductions in miR-26a and miR-26b, known regulators of EZH2 in some non-prostate cell types, albeit not in others. Further, in human prostate cancer cells, Myc negatively regulates miR-26a and miR-26b via direct binding to their parental Pol II gene promoters, and forced overexpression of miR-26a and miR-26b in prostate cancer cells results in decreased EZH2 levels and suppressed proliferation. In human clinical samples, miR-26a and miR-26b are downregulated in most primary prostate cancers. As a separate mechanism of EZH2 mRNA upregulation, we find that Myc binds directly to and activates the transcription of the EZH2 promoter. These results link two major pathways in prostate cancer by providing two additional and complementary Myc-regulated mechanisms by which EZH2 upregulation occurs and is enforced during prostatic carcinogenesis. Further, the results implicate EZH2-driven mechanisms by which Myc may stimulate prostate tumor initiation and disease progression.
EZH2是PRC2多梳抑制复合体的一部分,在多种癌症类型中过表达,并与前列腺癌的发生和发展有关。在此,我们确定EZH2是前列腺癌中MYC癌基因的一个靶点,并表明MYC通过转录和转录后手段协同调节EZH2。尽管先前对前列腺癌的研究已经揭示了EZH2上调的一些可能机制,但这些变化无法解释许多原发性前列腺癌以及大多数高级别前列腺上皮内瘤变(PIN)病例中EZH2的过表达。我们报告称,小鼠前列腺中Myc的上调导致EZH2 mRNA和蛋白的过表达,这与miR - 26a和miR - 26b的减少相一致,miR - 26a和miR - 26b在某些非前列腺细胞类型中是已知的EZH2调节因子,尽管在其他细胞类型中并非如此。此外,在人前列腺癌细胞中,Myc通过直接结合其亲本Pol II基因启动子对miR - 26a和miR - 26b进行负调控,在前列腺癌细胞中强制过表达miR - 26a和miR - 26b会导致EZH2水平降低和增殖受抑制。在人类临床样本中,大多数原发性前列腺癌中miR - 26a和miR - 26b下调。作为EZH2 mRNA上调的另一种机制,我们发现Myc直接结合并激活EZH2启动子的转录。这些结果通过提供另外两种互补的Myc调节机制,将前列腺癌中的两条主要通路联系起来,EZH2上调通过这些机制在前列腺癌发生过程中出现并得以维持。此外,这些结果暗示了EZH2驱动的机制,通过该机制Myc可能刺激前列腺肿瘤的起始和疾病进展。