DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1.
DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1.
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DOI：
10.1038/s41419-018-0585-y
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Wang QE
中科院分区：
文献类型：
--
作者：
Cui T;Srivastava AK;Han C;Wu D;Wani N;Liu L;Gao Z;Qu M;Zou N;Zhang X;Yi P;Yu J;Bell EH;Yang SM;Maloney DJ;Zheng Y;Wani AA;Wang QE
肿瘤干细胞（CSCs）是包括卵巢癌在内的许多实体肿瘤的根源，与疾病复发、转移和治疗耐药性有关。我们之前的研究表明，卵巢癌中的CSC亚群可能受到DNA损伤结合蛋白2 （DDB2）的限制。在这里，我们证明卵巢CSC亚群可以通过癌细胞去分化来维持，DDB2能够通过抑制ALDH1A1转录来抑制这种非CSC到CSC的转化。机制上，DDB2与ALDH1A1基因启动子结合，促进组蛋白H3K27me3的富集，并与转录因子C/EBPβ竞争与该区域的结合，最终抑制ALDH1A1基因启动子的活性。ALDH1A1表达的去抑制有助于DDB2沉默增强的非CSC到CSC的转换和CSC亚群的扩展。我们进一步表明，使用选择性ALDH1A1抑制剂治疗可阻断DDB2沉默诱导的CSCs扩增，并阻止原位异种移植物肿瘤生长。总之，我们的数据表明，DDB2作为一种转录抑制因子，可以通过下调ALDH1A1的表达来消除卵巢CSC的特性。
Cancer stem cells (CSCs), representing the root of many solid tumors including ovarian cancer, have been implicated in disease recurrence, metastasis, and therapeutic resistance. Our previous study has demonstrated that the CSC subpopulation in ovarian cancer can be limited by DNA damage-binding protein 2 (DDB2). Here, we demonstrated that the ovarian CSC subpopulation can be maintained via cancer cell dedifferentiation, and DDB2 is able to suppress this non-CSC-to-CSC conversion by repression of ALDH1A1 transcription. Mechanistically, DDB2 binds to the ALDH1A1 gene promoter, facilitating the enrichment of histone H3K27me3, and competing with the transcription factor C/EBPβ for binding to this region, eventually inhibiting the promoter activity of the ALDH1A1 gene. The de-repression of ALDH1A1 expression contributes to DDB2 silencing-augmented non-CSC-to-CSC conversion and expansion of the CSC subpopulation. We further showed that treatment with a selective ALDH1A1 inhibitor blocked DDB2 silencing-induced expansion of CSCs, and halted orthotopic xenograft tumor growth. Together, our data demonstrate that DDB2, functioning as a transcription repressor, can abrogate ovarian CSC properties by downregulating ALDH1A1 expression.
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DOI：
10.1158/1541-7786.mcr-13-0638
发表时间：
2014-05
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Han C;Zhao R;Liu X;Srivastava A;Gong L;Mao H;Qu M;Zhao W;Yu J;Wang QE
通讯作者：
Wang QE
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
在没有DNA损伤的情况下，XRCC5/6的染色质缔合取决于XPE基因产物DDB2。
影响因子：
3.3
作者：
Fantini D;Huang S;Asara JM;Bagchi S;Raychaudhuri P
通讯作者：
Raychaudhuri P
影响因子：
11.2
作者：
Li, Jinyou;Wang, Qi-En;Wani, Altaf A.
通讯作者：
Wani, Altaf A.
DOI：
10.1073/pnas.0603806103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Chute, John P.;Muramoto, Garrett G.;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.