DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.
DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.
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DNA甲基转移酶1使用瓜杜发可以通过凋亡独立的途径抑制前列腺癌的生长。
作者：
我们描述了guadecitabine （gDEC）激活赖氨酸甲基转移酶（KMTs）与前列腺癌抑制相关的独特作用。本研究表明，gDEC靶向dnmt1的一个后果是表观遗传激活酶的上调，从而促进前列腺癌整体表型改变和不依赖于细胞凋亡的抗癌作用。在机制上，gDEC增加前列腺癌细胞系中H3K4的单甲基化和二甲基化，并与DNMT1缺失有关。重要的是，用gDEC靶向dnmt1逆转肿瘤抑制程序的异常表观遗传抑制表明治疗前列腺癌的治疗潜力。表观遗传改变，如DNA甲基化和组蛋白修饰与抑制前列腺癌进展中的几种肿瘤抑制基因有关。在这项研究中，我们确定了一种小分子药物guadecitabine （gDEC）的抗前列腺癌作用，该药物抑制/耗尽DNA甲基化书写者DNA甲基转移酶1 （DNMT1）。gDEC在体外不激活凋亡级联的情况下抑制前列腺癌细胞的生长和增殖。分子研究证实，DNMT1缺失和上皮-间质转化标志物E-cadherin和β-catenin在几种前列腺癌细胞系（LNCaP、22Rv1和MDA PCa 2b）中被调节。gDEC治疗还能显著抑制小鼠体内前列腺肿瘤（22Rv1、MDA PCa 2b和PC-3异种移植物）的生长，没有观察到任何毒性。gDEC不影响雄激素受体（AR）或AR变体7 （AR- v7）的表达，也不使前列腺癌细胞对抗雄激素enzalutamide敏感。为了进一步研究gDEC的细胞减少机制，对84种染色质修饰酶的PCR阵列分析表明，几种赖氨酸特异性甲基转移酶（KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A）上调，并通过体外和采集的异种移植物的额外表达分析得到证实。此外，gDEC处理增加了整体组蛋白3赖氨酸4单甲基化和二甲基化（H3K4me1和H3K4me2）。综上所述，gDEC除了直接消耗协同抑制因子DNMT1外，还上调KMT激活表观遗传酶，激活末端上皮程序激活，以及独立于凋亡的前列腺癌细胞周期退出。
We describe the unique role of guadecitabine (gDEC) activating lysine methyltransferases (KMTs) in association with prostate cancer inhibition. This study suggests that one consequence of DNMT1-targeting by gDEC is the upregulation of epigenetic activating enzymes to contribute to the overall prostate cancer phenotype change and anticancer effect independent of apoptosis. Mechanistically, gDEC increases the mono- and di-methylation of H3K4 in prostate cancer cell lines and was associated with DNMT1 depletion. Importantly, DNMT1-targeting with gDEC to reverse aberrant epigenetic repression of tumor suppressor programs suggests the therapeutic potential of treating prostate cancer. Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade. Molecular studies confirmed DNMT1 depletion and modulated epithelial-mesenchymal transition markers E-cadherin and β-catenin in several prostate cancer cell lines (LNCaP, 22Rv1, and MDA PCa 2b). gDEC treatment also significantly inhibited prostate tumor growth in vivo in mice (22Rv1, MDA PCa 2b, and PC-3 xenografts) without any observed toxicities. gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. In further investigating the mechanism of cytoreduction by gDEC, a PCR array analyses of 84 chromatin modifying enzymes demonstrated upregulation of several lysine-specific methyltransferases (KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A), confirmed by additional expression analyses in vitro and of harvested xenografts. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.
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