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WDR61 ablation triggers R-loop accumulation and suppresses breast cancer progression
Yayan Hou1, Chunyong Zhang1, Ling Liu1
1State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, China.
Abstract:
Although, superkiller complex protein 8 (SKI8), previously known as WDR61 has been identified and mapped in breast tumor, little is currently known about its function. This study aims to elucidate the role of WDR61 in breast tumor development and its potential as a therapeutic target. Here, we show that tamoxifen-induced knockout of Wdr61 reduces the risk of breast tumors, resulting in smaller tumor size and weight, and improved overall survival. Furthermore, we show that knockdown of WDR61 compromises the proliferation of breast tumor cells with reduced colony-forming capacity. Further investigations demonstrate that the protective effect of WDR61 loss on breast tumor development is due to genomic instability. Mechanistic studies reveal that WDR61 interacts with the R-loop, and loss of WDR61 leads to R-loops accumulation in breast tumor cells, causing DNA damage and subsequent inhibition of cell proliferation. In summary, this study highlights the critical dependence of breast tumors on WDR61, which suppresses R-loop and counteracts endogenous DNA damage in tumor cells.
Insights
Superkiller complex protein 8 (SKI8), also known as WDR61, is crucial for breast tumor growth. Loss of WDR61 reduces tumor size and improves survival by causing genomic instability and DNA damage.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Superkiller complex protein 8 (SKI8), also known as WDR61, has been identified in breast tumors, but its function remains largely unknown.
- Understanding WDR61's role is critical for identifying new therapeutic targets in breast cancer.
Purpose of the Study:
- To elucidate the function of WDR61 in breast tumor development.
- To investigate the potential of WDR61 as a therapeutic target for breast cancer.
Main Methods:
- Tamoxifen-induced knockout and knockdown of Wdr61 in mouse models and cell lines.
- Assessment of tumor size, weight, cell proliferation, and colony-forming capacity.
- Analysis of genomic instability, DNA damage, and R-loop accumulation.
Main Results:
- Wdr61 knockout significantly reduced breast tumor risk, size, and weight, improving overall survival.
- WDR61 knockdown inhibited breast tumor cell proliferation and colony formation.
- Loss of WDR61 led to genomic instability and DNA damage due to R-loop accumulation.
Conclusions:
- Breast tumors critically depend on WDR61 for growth and survival.
- WDR61 plays a key role in suppressing R-loops and counteracting endogenous DNA damage in tumor cells.
- Targeting WDR61 represents a potential therapeutic strategy for breast cancer.
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