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.
Highlights
Ovarian cancer is the most lethal malignancy of the female reproductive tract with a poor 5-year survival rate of only 28% in advanced stages, at which, 60% of cases are diagnosed[1]
Given that the cancer stem cells (CSCs) subpopulation in a tumor can be maintained by non-CSC dedifferentiation[30,31], we attempted to determine whether non-CSC dedifferentiation exists in ovarian cancer cells, and whether
To functionally ascertain the effect of DNA damage-binding protein 2 (DDB2) silencing on the non-CSC-to-CSC conversion, we analyzed the sphere formation rate and the frequency of tumorinitiating cells (TICf) in the CD44−CD117− cells after
Summary
Ovarian cancer is the most lethal malignancy of the female reproductive tract with a poor 5-year survival rate of only 28% in advanced stages, at which, 60% of cases are diagnosed[1]. Identifying efficient ways to halt ovarian cancer progression is important to improving progression-. Over the past few years, growing evidence suggests that the presence of cancer stem cells (CSCs) is the most important trigger of tumor initiation and progression[3,4,5]. These CSCs, with enhanced tumorigenicity and chemoresistance, have been identified in a variety of solid tumors including ovarian cancer[6,7,8,9], and are considered to be responsible for treatment failure, tumor metastasis, and recurrence. Eradication of CSCs could be an effective way to improve therapeutic efficacy
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