Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling
Mu Xiao1, Fei Wang1, Nuo Chen1
1The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Abstract:
Loss of TGF-β growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-β signaling. The ability of SFPQ to suppress TGF-β responses depends on its prion-like domain (PrLD) that drives liquid-liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-β responses. Together, our data identify an important function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-β tumor-suppressive activity.
Insights
Splicing factor SFPQ suppresses transforming growth factor beta (TGF-β) signaling by sequestering Smad4 via liquid-liquid phase separation (LLPS). This mechanism contributes to cancer cells
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Loss of transforming growth factor beta (TGF-β) growth-inhibitory responses is a key characteristic of human cancers.
- The precise molecular mechanisms driving TGF-β resistance in cancer cells require further investigation.
Purpose of the Study:
- To identify molecular mechanisms by which cancer cells develop resistance to TGF-β signaling.
- To investigate the role of Splicing factor proline- and glutamine-rich (SFPQ) in regulating TGF-β responses.
Main Methods:
- Investigated the interaction between SFPQ and TGF-β signaling components.
- Utilized cell-based assays to assess TGF-β signaling activity.
- Examined the role of SFPQ's prion-like domain (PrLD) and liquid-liquid phase separation (LLPS) in regulating Smad4 function.
Main Results:
- SFPQ was identified as a potent suppressor of TGF-β signaling.
- SFPQ's ability to suppress TGF-β responses is dependent on its PrLD and LLPS activity.
- SFPQ sequesters Smad4 within its phase-separated condensates, preventing Smad complex formation and chromatin binding.
- SFPQ deficiency or impaired LLPS activity led to hypersensitivity to TGF-β responses.
Conclusions:
- SFPQ functions as a suppressor of TGF-β signaling through LLPS-driven sequestration of Smad4.
- This mechanism dampens Smad-dependent transcription and TGF-β's tumor-suppressive activity.
- Targeting SFPQ-mediated LLPS may offer a novel therapeutic strategy for overcoming TGF-β resistance in cancer.
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