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The PIAS3-Smurf2 sumoylation pathway suppresses breast cancer organoid invasiveness
Amrita Singh Chandhoke1, Ayan Chanda1, Kunal Karve1
1Department of Biochemistry and Molecular Biology, and The Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada, T2N 4N1.
Abstract:
Tumor metastasis profoundly reduces the survival of breast cancer patients, but the mechanisms underlying breast cancer invasiveness and metastasis are incompletely understood. Here, we report that the E3 ubiquitin ligase Smurf2 acts in a sumoylation-dependent manner to suppress the invasive behavior of MDA-MB-231 human breast cancer cell-derived organoids. We also find that the SUMO E3 ligase PIAS3 inhibits the invasive growth of breast cancer cell-derived organoids. In mechanistic studies, PIAS3 maintains breast cancer organoids in a non-invasive state via sumoylation of Smurf2. Importantly, the E3 ubiquitin ligase activity is required for sumoylated Smurf2 to suppress the invasive growth of breast cancer-cell derived organoids. Collectively, our findings define a novel role for the PIAS3-Smurf2 sumoylation pathway in the suppression of breast cancer cell invasiveness. These findings lay the foundation for the development of novel biomarkers and targeted therapeutic approaches in breast cancer.
Insights
The PIAS3-Smurf2 sumoylation pathway suppresses breast cancer cell invasiveness. This pathway is crucial for maintaining non-invasive breast cancer organoids, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer metastasis significantly impacts patient survival.
- The molecular mechanisms driving breast cancer invasiveness and metastasis remain incompletely understood.
Purpose of the Study:
- To investigate the role of the E3 ubiquitin ligase Smurf2 and SUMO E3 ligase PIAS3 in breast cancer cell invasiveness.
- To elucidate the molecular mechanisms by which PIAS3 and Smurf2 regulate breast cancer organoid behavior.
Main Methods:
- Utilized MDA-MB-231 human breast cancer cell-derived organoids.
- Investigated the sumoylation-dependent function of Smurf2.
- Examined the inhibitory effect of PIAS3 on invasive growth.
- Assessed the requirement of E3 ubiquitin ligase activity for Smurf2 function.
Main Results:
- Smurf2, in a sumoylation-dependent manner, suppresses the invasive behavior of breast cancer organoids.
- PIAS3 inhibits the invasive growth of breast cancer organoids.
- PIAS3 maintains non-invasive organoid states through the sumoylation of Smurf2.
- Sumoylated Smurf2 requires E3 ubiquitin ligase activity to inhibit invasive growth.
Conclusions:
- Identified a novel PIAS3-Smurf2 sumoylation pathway that suppresses breast cancer cell invasiveness.
- This pathway is critical for maintaining breast cancer organoids in a non-invasive state.
- Findings provide a foundation for developing new breast cancer biomarkers and targeted therapies.