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Published on: June 12, 2019
RNA-Binding Protein NF90 Mediates Polycomb-Independent Transactivation by EZH2 to Promote Cancer Growth
Abstract:
Increasing evidence suggests critical roles of the polycomb-independent transactivation function of EZH2 in promoting some cancers, such as prostate cancer (PCa), yet the underlying mechanism remains poorly understood. Here, we identify the RNA-binding protein NF90 as a key mediator of this activity. NF90 interacts with EZH2, but not with other core components of the polycomb repressive complex 2 (PRC2), through its RNA-binding modules. Conversely, EZH2 engages NF90 via its intrinsically disordered RNA-binding domain in an RNA-dependent manner. NF90 and EZH2 mutually recruit each other to the AR promoter, where they cooperatively activate AR transcription and enhance downstream AR signaling. This NF90-EZH2 complex is essential for PCa cell growth: depletion of either factor abolishes proliferation, an effect rescued by AR re-expression. Similar to EZH2, NF90 promotes cell-cycle gene expression, is upregulated in advanced PCa, and is associated with poor clinical outcomes. Collectively, our findings uncover RNA-mediated protein interactions as a central mechanism underlying PRC2-independent transcriptional activation by EZH2 and establish NF90 as a major EZH2 coactivator, a master regulator of the cell cycle, and a promising therapeutic target in advanced PCa.
Insights
The RNA-binding protein NF90 acts as a coactivator for EZH2, promoting prostate cancer (PCa) cell growth by activating androgen receptor (AR) signaling. This interaction, independent of Polycomb Repressive Complex 2 (PRC2), highlights NF90 as a potential therapeutic target in advanced PCa.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- EZH2 plays a role in cancer, but its non-canonical functions are not well understood.
- Prostate cancer (PCa) progression is linked to EZH2 activity.
- The mechanism of EZH2-mediated transactivation independent of Polycomb Repressive Complex 2 (PRC2) requires elucidation.
Purpose of the Study:
- To identify key mediators of EZH2's polycomb-independent transactivation function in prostate cancer.
- To elucidate the mechanism by which EZH2 promotes prostate cancer cell growth.
- To explore NF90 and EZH2 as potential therapeutic targets in advanced PCa.
Main Methods:
- Investigated protein-protein interactions between EZH2 and RNA-binding proteins.
- Utilized RNA immunoprecipitation to study EZH2 and NF90 recruitment to the AR promoter.
- Assessed the impact of NF90 and EZH2 depletion on PCa cell proliferation and AR signaling.
- Analyzed NF90 expression in relation to PCa clinical outcomes.
Main Results:
- Identified NF90 as an EZH2-interacting protein, binding through RNA.
- Demonstrated that NF90 and EZH2 mutually recruit to the AR promoter, enhancing AR transcription and signaling.
- Showed that depletion of NF90 or EZH2 inhibits PCa cell proliferation, which can be rescued by AR re-expression.
- Found NF90 to be upregulated in advanced PCa and associated with poor prognosis.
Conclusions:
- Uncovered RNA-mediated interactions as a mechanism for PRC2-independent EZH2 transcriptional activation.
- Established NF90 as a crucial coactivator of EZH2 and a master regulator of the cell cycle.
- Positioned NF90 as a promising therapeutic target for advanced prostate cancer.
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