Karan Dev, Singh Manohar, Dubey Seema, Van Veldhuizen Peter J, Saunthararajah Yogen
Department of Pathology, MCW Cancer Center, Prostate Cancer Center of Excellence, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Department of Internal Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cancers (Basel). 2023 May 15;15(10):2763. doi: 10.3390/cancers15102763.
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.
诸如DNA甲基化和组蛋白修饰等表观遗传改变与前列腺癌进展过程中多个肿瘤抑制基因的抑制有关。在本研究中，我们确定了一种小分子药物地西他滨（gDEC）的抗前列腺癌作用，该药物可抑制/消耗DNA甲基化写入酶DNA甲基转移酶1（DNMT1）。gDEC在体外抑制前列腺癌细胞的生长和增殖，而不激活凋亡级联反应。分子研究证实，在几种前列腺癌细胞系（LNCaP、22Rv1和MDA PCa 2b）中，DNMT1被消耗，并调节了上皮-间质转化标志物E-钙黏蛋白和β-连环蛋白。gDEC治疗还显著抑制了小鼠体内的前列腺肿瘤生长（22Rv1、MDA PCa 2b和PC-3异种移植物），且未观察到任何毒性。gDEC在体外不影响雄激素受体（AR）或AR变体7（AR-V7）的表达，也不会使前列腺癌细胞对抗雄激素恩杂鲁胺敏感。在进一步研究gDEC的细胞减灭机制时，对84种染色质修饰酶进行的PCR阵列分析显示，几种赖氨酸特异性甲基转移酶（KMTs：KMT2A、KMT2C、KMT2E、KMT2H、KMT5A）上调，体外和收获的异种移植物中的额外表达分析证实了这一点。此外，gDEC治疗增加了整体组蛋白3赖氨酸4单甲基化和二甲基化（H3K4me1和H3K4me2）。总之，gDEC除了直接消耗共抑制因子DNMT1外，还上调了激活表观遗传酶的KMT，激活终末上皮程序激活，并使前列腺癌细胞周期退出，且不依赖于凋亡。
