Low-dose DNA demethylating therapy induces reprogramming of diverse cancer-related pathways at the single-cell level.
Low-dose DNA demethylating therapy induces reprogramming of diverse cancer-related pathways at the single-cell level.
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低剂量DNA去甲基化治疗在单细胞水平诱导多种癌症相关通路的重编程。
DOI：
10.1186/s13148-020-00937-y
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发表时间：
2020-09-21
影响因子：
5.7
通讯作者：
Ushijima T
中科院分区：
文献类型：
--
作者：
Takeshima H;Yoda Y;Wakabayashi M;Hattori N;Yamashita S;Ushijima T
使用DNA去甲基化药物的表观遗传重编程是一种有前途的癌症治疗方法，但其疗效高度依赖于给药方案。长期低剂量治疗显示出显著的治疗效果，尽管其去甲基化作用很小。在这里，我们的目标是通过关注单细胞水平的表观遗传重编程来探索这种低剂量治疗如何显示出这种显着功效的机制。通过单细胞RNA测序（scRNA-seq）分析用地西他滨（DAC）处理的HCT 116细胞中的表达谱。使用DAC处理后的克隆HCT 116细胞分析单细胞水平的功能后果和DNA去甲基化。scRNA-seq显示，DAC处理的细胞在单细胞水平上具有高度多样的表达谱，并且肿瘤抑制基因、内源性逆转录病毒和干扰素刺激的基因在细胞的随机部分中上调。克隆的HCT 116细胞的DNA甲基化分析显示，虽然在本体细胞中仅观察到DNA甲基化水平的部分降低，但观察到特定癌症相关基因的完全去甲基化，如细胞周期调控、WNT通路、p53通路和TGF-β通路，这取决于克隆。在功能上，具有完全去甲基化的CDKN 2A（p16）的克隆具有比亲本细胞更大的四倍体细胞分数，表明由于细胞周期调节的正常化而诱导细胞衰老。在单细胞水平上对特定癌症相关通路的表观遗传重编程可能是低剂量DNA去甲基化治疗显著疗效的基础。
Epigenetic reprogramming using DNA demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a remarkable therapeutic efficacy, despite its small demethylating effect. Here, we aimed to explore the mechanisms of how such low-dose treatment shows this remarkable efficacy by focusing on epigenetic reprograming at the single-cell level. Expression profiles in HCT116 cells treated with decitabine (DAC) were analyzed by single-cell RNA-sequencing (scRNA-seq). Functional consequences and DNA demethylation at the single-cell level were analyzed using cloned HCT116 cells after DAC treatment. scRNA-seq revealed that DAC-treated cells had highly diverse expression profiles at the single-cell level, and tumor-suppressor genes, endogenous retroviruses, and interferon-stimulated genes were upregulated in random fractions of cells. DNA methylation analysis of cloned HCT116 cells revealed that, while only partial reduction of DNA methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes, such as cell cycle regulation, WNT pathway, p53 pathway, and TGF-β pathway, was observed, depending upon clones. Functionally, a clone with complete demethylation of CDKN2A (p16) had a larger fraction of cells with tetraploid than parental cells, indicating induction of cellular senescence due to normalization of cell cycle regulation. Epigenetic reprogramming of specific cancer-related pathways at the single-cell level is likely to underlie the remarkable efficacy of low-dose DNA demethylating therapy.
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DOI：
10.1158/1078-0432.ccr-16-1896
发表时间：
2017-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Schneider BJ;Shah MA;Klute K;Ocean A;Popa E;Altorki N;Lieberman M;Schreiner A;Yantiss R;Christos PJ;Palmer R;You D;Viale A;Kermani P;Scandura JM
通讯作者：
Scandura JM
影响因子：
64.8
作者：
Lu Z;Zou J;Li S;Topper MJ;Tao Y;Zhang H;Jiao X;Xie W;Kong X;Vaz M;Li H;Cai Y;Xia L;Huang P;Rodgers K;Lee B;Riemer JB;Day CP;Yen RC;Cui Y;Wang Y;Wang Y;Zhang W;Easwaran H;Hulbert A;Kim K;Juergens RA;Yang SC;Battafarano RJ;Bush EL;Broderick SR;Cattaneo SM;Brahmer JR;Rudin CM;Wrangle J;Mei Y;Kim YJ;Zhang B;Wang KK;Forde PM;Margolick JB;Nelkin BD;Zahnow CA;Pardoll DM;Housseau F;Baylin SB;Shen L;Brock MV
通讯作者：
Brock MV
影响因子：
5.8
作者：
Pechalrieu, Dany;Etievant, Chantal;Arimondo, Paola B.
通讯作者：
Arimondo, Paola B.
DOI：
10.1073/pnas.93.24.13742
发表时间：
1996-11-26
影响因子：
11.1
作者：
Alcorta, DA;Xiong, Y;Barrett, JC
通讯作者：
Barrett, JC
低剂量地西他滨引发的化学免疫疗法治疗耐药复发/难治性消化道癌患者的安全性和有效性的 Ib/II 期研究
影响因子：
6.4
作者：
Chen M;Nie J;Liu Y;Li X;Zhang Y;Brock MV;Feng K;Wu Z;Li X;Shi L;Li S;Guo M;Mei Q;Han W
通讯作者：
Han W