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

TitleDDX5 regulates DNA replication and is required for cell proliferation in a subset of breast cancer cells.
Publication TypeJournal Article
Year of Publication2012
AuthorsMazurek A, Luo W, Krasnitz A, Hicks J, R Powers S, Stillman B
JournalCancer Discov
Volume2
Issue9
Pagination812-25
Date Published2012 Sep
ISSN2159-8290
KeywordsBreast Neoplasms, Cell Growth Processes, Cell Line, Tumor, DEAD-box RNA Helicases, DNA, Neoplasm, DNA Replication, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Molecular Targeted Therapy, Plasmids, Promoter Regions, Genetic, RNA Polymerase II, S Phase
Abstract

<p><b>UNLABELLED: </b>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.</p><p><b>SIGNIFICANCE: </b>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 amplified, and this has uncovered a dependence on DDX5 for cell proliferation. Given the high frequency of DDX5 amplification in breast cancer, our results highlight DDX5 as a promising candidate for targeted therapy of breast tumors with DDX5 amplification, and indeed we show that DDX5 inhibition sensitizes a subset of breast cancer cells to trastuzumab.</p>

DOI10.1158/2159-8290.CD-12-0116
Alternate JournalCancer Discov
PubMed ID22750847
PubMed Central IDPMC3440546
Grant ListCA13106 / CA / NCI NIH HHS / United States
CA45508 / CA / NCI NIH HHS / United States
R01 CA124648 / CA / NCI NIH HHS / United States
P30 CA045508 / CA / NCI NIH HHS / United States
CA124648 / CA / NCI NIH HHS / United States
P01 CA013106 / CA / NCI NIH HHS / United States