Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma
Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma
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DOI：
10.1002/hep.31642
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发表时间：
2021-06-01
期刊：
影响因子：
13.5
通讯作者：
Avila, Matias A.
中科院分区：
文献类型：
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作者：
Colyn, Leticia;Barcena-Varela, Marina;Avila, Matias A.
背景和目的胆管癌（CCA）是一种毁灭性的疾病，往往发现在晚期时，不能进行手术。常规和靶向全身治疗效果不佳，因此迫切需要有效的药物。不同的表观遗传修饰发生在CCA中，并导致恶性肿瘤。因此，靶向表观遗传机制可能会打开治疗机会。然而，DNA和组蛋白甲基化等修饰在致癌作用中往往共存并协同作用。我们测试了一类双重G9 a组蛋白甲基转移酶和DNA甲基转移酶1（DNMT 1）抑制剂的治疗效果和作用机制。方法和结果G9 a、DNMT 1及其分子衔接子、具有PHD和RING指结构域的泛素样蛋白1（UHRF 1）在人CCA中的表达。我们评估了G9 a和DNMT 1单独和联合药理学抑制对CCA细胞生长的影响。我们的主要G9 a/DNMT 1抑制剂CM 272在人CCA细胞、患者来源的类肿瘤和异种移植物以及具有c-Jun-N-末端激酶（Jnk）-1/2和二乙基亚硝胺（DEN）的肝细胞缺失的胆管癌发生的小鼠模型加CCl 4处理（Jnk（Delta hepa）+ DEN + CCl 4小鼠）中进行了测试。G9 a、DNMT 1和UHRF 1在CCA中的表达增加且相关。与独立的药理学抑制剂G9 a和DNMT 1协同处理抑制CCA细胞生长。CM 272显著降低CCA细胞增殖，并与顺铂和ERBB靶向抑制剂拉帕替尼协同作用。CM 272抑制CCA类肿瘤和异种移植物生长，并显著拮抗JNK（Delta hepa）+ DEN + CCl 4小鼠的CCA进展，而无明显毒性。机械，CM 272重新编程肿瘤代谢转录组和表型向分化和静止status.Conclusions双靶向G9 a和DNMT 1与表观遗传小分子抑制剂，如CM 272是一个潜在的战略，以治疗CCA和/或提高其他系统治疗的疗效。
Background and Aims Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors.Approach and Results Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl4 treatment (Jnk(Delta hepa) + DEN + CCl4 mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in Jnk(Delta hepa) + DEN + CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status.Conclusions Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.