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Updated: Jan 25, 2026
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1
Huan He1, Dandan Song1, Indranil Sinha1
1Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83, Huddinge, Sweden.
Abstract:
Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor growth. Here we report the identification of 118 proteins interacting with endogenous chromatin-bound Fra-1 in TNBC cells, highlighting DDX5 as the most enriched Fra-1-interacting protein. DDX5, a previously unrecognized protein in the Fra-1 transcriptional network, shows extensive overlap with Fra-1 cistrome and transcriptome that are highly associated with the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity and potentiates Fra-1-driven cell proliferation. Furthermore, we show that the DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal-like tumors than in non-basal-like tumors, including luminal A, luminal B, and HER2-enriched subtypes. Collectively, by combining proteomic and genomic approaches we reveal a role for DDX5 as a regulatory protein of Fra-1 signaling and suggest DDX5 as a potential therapeutic target for TNBC.
Insights
The activator protein 1 (AP-1) family member Fra-1 is overexpressed in triple-negative breast cancer (TNBC). Researchers identified DDX5 as a key interacting protein, revealing DDX5 as a potential therapeutic target for TNBC.
Area of Science:
- Molecular Biology
- Oncology
- Proteomics
Background:
- Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC).
- Fra-1 plays crucial roles in tumor growth and progression within TNBC.
- The precise molecular mechanisms governing Fra-1's function in TNBC are not fully elucidated.
Purpose of the Study:
- To identify proteins interacting with endogenous chromatin-bound Fra-1 in TNBC cells.
- To investigate the functional role of DDX5 in Fra-1 transcriptional activity and TNBC cell proliferation.
- To evaluate DDX5 as a potential therapeutic target for TNBC.
Main Methods:
- Proteomic analysis to identify Fra-1 interacting proteins.
- Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to analyze Fra-1 and DDX5 cistromes and transcriptomes.
- Functional assays to assess the impact of DDX5 on Fra-1 activity and cell proliferation.
- Analysis of DDX5 expression in breast cancer patient cohorts.
Main Results:
- 118 proteins were identified interacting with Fra-1, with DDX5 being the most enriched.
- DDX5 shows extensive overlap with Fra-1 cistrome and transcriptome, correlating with TNBC cell growth.
- DDX5 expression enhances Fra-1 transcriptional activity and potentiates Fra-1-driven proliferation.
- A DDX5 target gene signature predicts poor clinical outcomes in breast cancer patients.
- DDX5 protein levels are significantly higher in triple-negative basal-like tumors compared to other subtypes.
Conclusions:
- DDX5 is a novel regulator of Fra-1 signaling in TNBC.
- DDX5 potentiates Fra-1-driven TNBC cell growth and proliferation.
- DDX5 represents a promising potential therapeutic target for triple-negative breast cancer.
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