title: DDB2 modulates TGF-β signal transduction in human ovarian cancer cells by downregulating NEDD4L.
abstract: The expression of DNA damage-binding protein 2 (DDB2) has been linked to the prognosis of ovarian cancer and its underlying transcription regulatory function was proposed to contribute to the favorable treatment outcome. By applying gene microarray analysis, we discovered neural precursor cell expressed, developmentally downregulated 4-Like (NEDD4L) as a previously unidentified downstream gene regulated by DDB2. Mechanistic investigation demonstrated that DDB2 can bind to the promoter region of NEDD4L and recruit enhancer of zeste homolog 2 histone methyltransferase to repress NEDD4L transcription by enhancing histone H3 lysine 27 trimethylation (H3K27me3) at the NEDD4L promoter. Given that NEDD4L plays an important role in constraining transforming growth factor β signaling by targeting activated Smad2/Smad3 for degradation, we investigated the role of DDB2 in the regulation of TGF-β signaling in ovarian cancer cells. Our data indicate that DDB2 enhances TGF-β signal transduction and increases the responsiveness of ovarian cancer cells to TGF-β-induced growth inhibition. The study has uncovered an unappreciated regulatory mode that hinges on the interaction between DDB2 and NEDD4L in human ovarian cancer cells. The novel mechanism proposes the DDB2-mediated fine-tuning of TGF-β signaling and its downstream effects that impinge upon tumor growth in ovarian cancers.
authors.affiliation: Division of Radiobiology, Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Division of Radiobiology, Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Cui
authors.affiliation: Division of Radiobiology, Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Han
authors.affiliation: Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Radiobiology, Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Jinshan
authors.initials: J
authors.lastname: He
authors.affiliation: Division of Radiobiology, Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Radiobiology, Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Wani
authors.affiliation: Division of Radiobiology, Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA qi-en.wang@osumc.edu.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D000075702:Nedd4 Ubiquitin Protein Ligases; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D006657:Histones; D016212:Transforming Growth Factor beta; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases