DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1

Cell Death & Disease
Tiantian CuiQi-En Wang

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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Citations

Sep 5, 2018·BMC Cancer·Fan FengHongwei Zhang
Oct 23, 2019·International Journal of Molecular Sciences·Pauline GilsonAlexandre Harlé
Apr 8, 2020·Frontiers in Oncology·Nastassja TerraneoJürgen Grünberg
Apr 17, 2020·Cancers·Vaishnavi MuralikrishnanKenneth P Nephew

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Methods Mentioned

BETA
fluorescence-activated cell sorting
xenograft
immunoprecipitation
electrophoretic mobility shift assay
ChIP
reverse-transcription
transfection
xenografts
FACS
PCR

Software Mentioned

ELDA

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