Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation.
Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation.
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DOI：
10.1038/s41389-018-0092-0
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发表时间：
2018-10-11
期刊：
影响因子：
6.2
通讯作者：
Miotto B
中科院分区：
文献类型：
--
作者：
Marchal C;de Dieuleveult M;Saint-Ruf C;Guinot N;Ferry L;Olalla Saad ST;Lazarini M;Defossez PA;Miotto B
DNA甲基转移酶抑制剂（DNMTi）治疗已用于骨髓增生异常综合征（MDS）和急性髓性白血病（AML）患者，并已在一些其他类型的癌症中显示出有希望的有益效果。在这里，我们证明了转录抑制子ZBTB 38是细胞对DNMTi反应的关键调节因子。用5-氮杂胞苷或其衍生物地西他滨和zebularine治疗导致癌细胞中ZBTB 38蛋白表达下调，与细胞损伤平行。通过RNA干扰消除ZBTB 38增强了DNMTi在来自白血病和来自各种实体瘤类型的细胞系中的毒性。此外，我们观察到ZBTB 38的失活导致CDKN 1C mRNA的上调，CDKN 1C mRNA是先前描述的DNMTi的间接靶标。我们表明，CDKN 1C是缺乏ZBTB 38的细胞中DNMTi毒性的关键因素。最后，在MDS患者中，治疗前高水平的CDKN 1C mRNA表达与对5-氮杂胞苷和组蛋白去乙酰化酶抑制剂联合用药方案的更好临床反应相关。总的来说，我们的研究结果表明，ZBTB 38蛋白是DNMTi的靶点，其耗尽增强了DNMT抑制剂在癌细胞中的毒性，为增强MDS和其他癌症患者对DNMT抑制剂治疗的反应提供了新的机会。
DNA methyltransferase inhibitor (DNMTi) treatments have been used for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and have shown promising beneficial effects in some other types of cancers. Here, we demonstrate that the transcriptional repressor ZBTB38 is a critical regulator of the cellular response to DNMTi. Treatments with 5-azacytidine, or its derivatives decitabine and zebularine, lead to down-regulation of ZBTB38 protein expression in cancer cells, in parallel with cellular damage. The depletion of ZBTB38 by RNA interference enhances the toxicity of DNMTi in cell lines from leukemia and from various solid tumor types. Further we observed that inactivation of ZBTB38 causes the up-regulation of CDKN1C mRNA, a previously described indirect target of DNMTi. We show that CDKN1C is a key actor of DNMTi toxicity in cells lacking ZBTB38. Finally, in patients with MDS a high level of CDKN1C mRNA expression before treatment correlates with a better clinical response to a drug regimen combining 5-azacytidine and histone deacetylase inhibitors. Collectively, our results suggest that the ZBTB38 protein is a target of DNMTi and that its depletion potentiates the toxicity of DNMT inhibitors in cancer cells, providing new opportunities to enhance the response to DNMT inhibitor therapies in patients with MDS and other cancers.
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影响因子：
3.7
作者：
Buck-Koehntop BA;Defossez PA
通讯作者：
Defossez PA
影响因子：
3.7
作者：
Hagemann S;Heil O;Lyko F;Brueckner B
通讯作者：
Brueckner B
影响因子：
4.6
作者：
Kotoku T;Kosaka K;Nishio M;Ishida Y;Kawaichi M;Matsuda E
通讯作者：
Matsuda E
DOI：
10.1073/pnas.1216922110
发表时间：
2013-01-02
影响因子：
11.1
作者：
Leonova, Katerina I.;Brodsky, Leonid;Gudkov, Andrei V.
通讯作者：
Gudkov, Andrei V.
影响因子：
--
作者：
Fenaux, Pierre
通讯作者：
Fenaux, Pierre