Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
Leidos Biomedical Research, Inc., Frederick, MD, USA.
Sci Rep. 2023 Apr 12;13(1):5964. doi: 10.1038/s41598-023-32509-4.
Role of DNA damage and demethylation on anticancer activity of DNA methyltransferase inhibitors (DNMTi) remains undefined. We report the effects of DNMT1 gene deletion/disruption (DNMT1) on anticancer activity of a class of DNMTi in vitro, in vivo and in human cancers. The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. The drugs induced DNA damage that concurred with DNMT1 inhibition, subsequent G/M cell-cycle arrest and apoptosis, and upregulated p21 in DNMT1 versus DNMT1 status, with aza-T-dCyd the most potent. Tumor growth and DNMT1 were significantly inhibited, and p21 was upmodulated in mice bearing HCT116 DNMT1 xenograft and bladder PDX tumors. DNMT1 gene deletion occurred in ~ 9% human colon cancers and other cancer types at varying degrees. Decitabine and azacitidine demethylated CDKN2A/CDKN2B genes in DNMT1 and DNMT1 conditions and increased histone-H3 acetylation with re-expression of p16/p15 in DNMT1 state. Thus, DNMT1 deletion confers resistance to DNMTi, and their anti-cancer activity is determined by DNA damage effects. Patients with DNMT1 gene deletions may not respond to DNMTi treatment.
DNA 损伤和去甲基化在 DNA 甲基转移酶抑制剂 (DNMTi) 的抗癌活性中的作用仍未确定。我们报告了 DNMT1 基因缺失/破坏 (DNMT1) 对体外、体内和人类癌症中一类 DNMTi 的抗癌活性的影响。基因缺失显著减弱了地西他滨、阿扎胞苷和 5-氮杂-4'-硫代-2'-脱氧胞苷 (aza-T-dCyd) 在结肠和乳腺癌细胞中的细胞毒性和生长抑制作用。这些药物诱导的 DNA 损伤与 DNMT1 抑制、随后的 G2/M 细胞周期停滞和细胞凋亡一致，并在上调 p21 方面，aza-T-dCyd 最为有效。在携带 HCT116 DNMT1 异种移植和膀胱 PDX 肿瘤的小鼠中，肿瘤生长和 DNMT1 显著受到抑制，p21 上调。在大约 9%的人类结肠癌和其他癌症类型中，DNMT1 基因缺失发生在不同程度。地西他滨和阿扎胞苷在 DNMT1 和 DNMT1 条件下使 CDKN2A/CDKN2B 基因去甲基化，并增加组蛋白-H3 乙酰化，同时在 DNMT1 状态下重新表达 p16/p15。因此，DNMT1 缺失赋予对 DNMTi 的耐药性，其抗癌活性取决于 DNA 损伤的影响。DNMT1 基因缺失的患者可能对 DNMTi 治疗无反应。
