DDX5 regulates DNA replication and is required for cell proliferation in a subset of breast cancer cells

Mazurek, A., Luo, W., Krasnitz, A., Hicks, J., Powers, R. S., Stillman, B. (2012) DDX5 regulates DNA replication and is required for cell proliferation in a subset of breast cancer cells. Cancer Discovery, 2 (9). pp. 812-825. ISSN 21598274 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/22750847
DOI: 10.1158/2159-8290.cd-12-0116

Abstract

Understanding factors required for DNA replication will enrich our knowledge of this important process and potentially identify vulnerabilities that can be exploited in cancer therapy. We applied an assay that measures the stability of maintenance of an episomal plasmid in human tissue culture cells to screen for new DNA replication factors. We identify an important role for DDX5 in G 1 -S-phase progression where it directly regulates DNA replication factor expression by promoting the recruitment of RNA polymerase II to E2F-regulated gene promoters. We find that the DDX5 locus is frequently amplified in breast cancer and that breast cancer-derived cells with amplification of DDX5 are much more sensitive to its depletion than breast cancer cells and a breast epithelial cell line that lacks DDX5 amplification. Our results show a novel role for DDX5 in cancer cell proliferation and suggest DDX5 as a therapeutic target in breast cancer treatment. SIGNIFICANCE: DDX5 is required for cell proliferation by controlling the transcription of genes expressing DNA replication proteins in cancer cells in which the DDX5 locus is amplifi ed, and this has uncovered a dependence on DDX5 for cell proliferation. Given the high frequency of DDX5 amplifi cation in breast cancer, our results highlight DDX5 as a promising candidate for targeted therapy of breast tumors with DDX5 amplifi cation, and indeed we show that DDX5 inhibition sensitizes a subset of breast cancer cells to trastuzumab. ©2012 American Association for Cancer Research.

Item Type: Paper
Uncontrolled Keywords: cycline DEAD box protein puromycin RNA polymerase II small interfering RNA transcription factor E2F2 trastuzumab article breast cancer cell cycle G1 phase cell proliferation chemosensitivity chromatin chromosome 17 colony formation controlled study copy number variation DNA replication flow cytometry G1 phase cell cycle checkpoint gene amplification gene expression gene locus human human cell immunoprecipitation microarray analysis polymerase chain reaction protein expression protein phosphorylation transcription regulation Western blotting Breast Neoplasms Cell Growth Processes Cell Line, Tumor DEAD-box RNA Helicases DNA, Neoplasm Female Gene Expression Regulation, Neoplastic HCT116 Cells Humans Molecular Targeted Therapy Plasmids Promoter Regions, Genetic S Phase
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA replication
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > cancer > cancer types > breast cancer
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Histology Service
CSHL Cancer Center Shared Resources > Instrumentation Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL Post Doctoral Fellows
CSHL labs > Hicks lab
CSHL labs > Krasnitz lab
CSHL labs > Powers lab
CSHL labs > Stillman lab
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
Highlight: Stillman, Bruce W.
Depositing User: Matt Covey
Date Deposited: 08 Mar 2013 18:29
Last Modified: 29 Oct 2015 20:18
PMCID: PMC3440546
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27734

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