DNMT3a-dermatopontin axis suppresses breast cancer malignancy via inactivating YAP
Danrong Ye1, Yuying Wang1, Xiaochong Deng2
1Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Abstract:
Breast cancer (BC) is the most common malignant tumor in women worldwide, and its recurrence and metastasis negatively affect patient prognosis. However, the mechanisms underlying its tumorigenesis and progression remain unclear. Recently, the influence of dermatopontin (DPT), which is an extracellular matrix protein, has been proposed in the development of cancer. Here we found that DNMT3a-mediated DPT, promoter hypermethylation results in the downregulation of DPT expression in breast cancer and its low expression correlated with poor prognosis. Notably, DPT directly interacted with YAP to promote YAP Ser127 phosphorylation, and restricted the translocation of endogenous YAP from the cytoplasm to the nucleus, thereby suppressing malignant phenotypes in BC cells. In addition, Ectopic YAP overexpression reversed the inhibitory effects of DPT on BC growth and metastasis. Our study showed the critical role of DPT in regulating BC progression, making it easier to explore the clinical potential of modulating DPT/YAP activity in BC targeted therapies.
Insights
Dermatopontin (DPT) downregulation, caused by DNA methylation, worsens breast cancer (BC) prognosis. DPT inhibits BC growth and metastasis by interacting with YAP, suggesting DPT/YAP modulation as a potential therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Breast cancer (BC) is a leading cause of cancer mortality in women globally.
- Tumorigenesis and progression mechanisms in BC require further elucidation.
- Dermatopontin (DPT), an extracellular matrix protein, is implicated in cancer development.
Purpose of the Study:
- To investigate the role of dermatopontin (DPT) in breast cancer (BC) progression.
- To elucidate the regulatory mechanisms of DPT expression in BC.
- To explore the interaction between DPT and YAP in BC pathogenesis.
Main Methods:
- Analysis of DPT promoter hypermethylation mediated by DNMT3a.
- Correlation of DPT expression levels with patient prognosis.
- Investigation of DPT's interaction with YAP and its effect on YAP translocation.
- Assessment of YAP overexpression effects on BC cell growth and metastasis.
Main Results:
- DNMT3a-mediated DPT promoter hypermethylation leads to DPT downregulation in BC.
- Low DPT expression correlates significantly with poor BC prognosis.
- DPT interacts with YAP, promoting YAP phosphorylation and inhibiting its nuclear translocation.
- Ectopic YAP overexpression counteracts DPT's inhibitory effects on BC growth and metastasis.
Conclusions:
- DPT plays a critical role in suppressing malignant phenotypes in breast cancer.
- DPT functions by inhibiting YAP nuclear translocation, thereby controlling BC progression.
- Modulating the DPT/YAP pathway presents a potential therapeutic strategy for breast cancer.
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