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Downregulated circPOKE promotes breast cancer metastasis through activation of the USP10-Snail axis
Yan Luo1, Qingyun Zhu1, Shasha Xiang1
1Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
Abstract:
Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among females. Metastasis accounts for the majority of BC related deaths. One feasible strategy to solve this challenging problem is to disrupt the capabilities required for tumor metastasis. Herein, we verified a novel metastasis suppressive circRNA, circPOKE in BC. circPOKE was downregulated in primary and metastatic BC tissues and overexpression of circPOKE inhibited the metastatic potential but not the proliferative ability of BC cells in vitro and in vivo. Mechanistically, circPOKE competitively binds to USP10, and reduces its binding to Snail, a key transcriptional regulator of EMT, thereby inhibiting Snail stability via the protein-ubiquitination degradation pathway. In addition, we found that circPOKE could be secreted into the extracellular space via exosomes and that exosome-carried circPOKE significantly inhibited the invasive capabilities of BC cells in vitro and in vivo. Furthermore, the levels of circPOKE, USP10 and Snail are clinically relevant in BC, suggesting that circPOKE may be used as a potential therapeutic target for patients with BC metastasis.
Insights
This study identifies circPOKE as a novel breast cancer (BC) metastasis suppressor. Lower circPOKE levels correlate with BC metastasis, and its restoration inhibits cancer spread by targeting the USP10-Snail pathway.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Breast cancer (BC) is a leading cause of cancer death in women, with metastasis being the primary driver of mortality.
- Targeting metastatic capabilities presents a crucial strategy for improving BC patient outcomes.
- Circular RNAs (circRNAs) are emerging as key regulators in cancer progression, including metastasis.
Purpose of the Study:
- To investigate the role of circPOKE as a potential suppressor of breast cancer metastasis.
- To elucidate the molecular mechanism by which circPOKE inhibits BC cell metastasis.
- To assess the clinical relevance of circPOKE, USP10, and Snail in breast cancer patients.
Main Methods:
- Quantitative real-time PCR and Western blotting to assess circPOKE, USP10, and Snail expression in BC tissues and cells.
- In vitro and in vivo assays to evaluate the effect of circPOKE overexpression on BC cell proliferation and metastasis.
- Co-immunoprecipitation and ubiquitination assays to determine the interaction between circPOKE, USP10, and Snail.
- Exosome isolation and characterization to study the secretion and function of exosomal circPOKE.
Main Results:
- circPOKE was significantly downregulated in primary and metastatic BC tissues compared to normal tissues.
- Overexpression of circPOKE suppressed BC cell invasion and metastasis in vitro and in vivo, without affecting proliferation.
- circPOKE competitively bound to USP10, inhibiting USP10's deubiquitinase activity towards Snail, thus promoting Snail degradation.
- Exosome-mediated transfer of circPOKE effectively inhibited BC cell invasiveness.
- circPOKE, USP10, and Snail expression levels showed significant clinical relevance in BC patients.
Conclusions:
- circPOKE acts as a novel suppressor of breast cancer metastasis by destabilizing the key EMT regulator Snail via the USP10-mediated ubiquitination pathway.
- Exosomal circPOKE plays a role in inhibiting BC cell invasion, suggesting intercellular communication in metastasis.
- circPOKE represents a potential therapeutic target for combating breast cancer metastasis.
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