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Cell Death Dis. 2018 May 1;9(5):561. doi: 10.1038/s41419-018-0585-y.

DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1.

Author information

1
Department of Radiology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
2
Department of Biotechnology, CSIR-North East Institute of Science and Technology (CSIR-NEIST), Jorhat, Assam, 785006, India.
3
Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
4
Oncology Center, Zhujiang Hospital, Southern Medical University, 510282, Guangdong, Guangzhou, China.
5
Department of Cell Biology, Weifang Medical University, 264053, Shandong, Weifang, China.
6
Department of Pharmacology, Weifang Medical University, 264053, Shandong, Weifang, China.
7
Department of Radiation Oncology, Hubei Cancer Hospital, 430079, Hubei, Wuhan, China.
8
Center for Biostatistics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
9
Department of Obstetrics and Gynecology, Daping Hospital, The Third Military Medical University, 40042, Chongqing, China.
10
Department of Internal Medicine, Division of Hematology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
11
Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
12
National Center for Advancing Translational Science, National Institutes of Health, Rockville, MD, 20850, USA.
13
Department of Radiology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA. wang.771@osu.edu.

Abstract

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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