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Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences
Undraga Schagdarsurengin1, Antje M Richter, Juliane Hornung
1Institute for Genetics, Justus-Liebig-University Giessen, Germany.
Background:
The Ras association domain family (RASSF) encodes for distinct tumor suppressors and several members are frequently silenced in human cancer. In our study, we analyzed the role of RASSF2, RASSF3, RASSF4, RASSF5A, RASSF5C and RASSF6 and the effectors MST1, MST2 and WW45 in thyroid carcinogenesis.
Results:
Frequent methylation of the RASSF2 and RASSF5A CpG island promoters in thyroid tumors was observed. RASSF2 was methylated in 88% of thyroid cancer cell lines and in 63% of primary thyroid carcinomas. RASSF2 methylation was significantly increased in primary thyroid carcinoma compared to normal thyroid, goiter and follicular adenoma (0%, 17% and 0%, respectively; p < 0.05). Patients which were older than 60 years were significantly hypermethylated for RASSF2 in their primary thyroid tumors compared to those younger than 40 years (90% vs. 38%; p < 0.05). RASSF2 promoter hypermethylation correlated with its reduced expression and treatment with a DNA methylation inhibitor reactivated RASSF2 transcription. Over-expression of RASSF2 reduced colony formation of thyroid cancer cells. Functionally our data show that RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines. Deletion of the MST interaction domain of RASSF2 reduced apoptosis significantly (p < 0.05).
Conclusion:
These results suggest that RASSF2 encodes a novel epigenetically inactivated candidate tumor suppressor gene in thyroid carcinogenesis.
Insights
The Ras association domain family protein 2 (RASSF2) gene is frequently silenced in thyroid cancer through promoter hypermethylation. Reactivating RASSF2 expression suppresses tumor growth and induces apoptosis, identifying it as a key tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- The Ras association domain family (RASSF) genes encode tumor suppressors, with several members frequently silenced in human cancers.
- This study investigates the roles of RASSF2, RASSF3, RASSF4, RASSF5A, RASSF5C, and RASSF6, along with effectors MST1, MST2, and WW45, in thyroid carcinogenesis.
Purpose of the Study:
- To analyze the involvement of RASSF family members and their effectors in thyroid cancer development.
- To determine the epigenetic regulation, specifically promoter methylation, of RASSF genes in thyroid tumors.
- To elucidate the functional role of RASSF2 as a potential tumor suppressor in thyroid carcinogenesis.
Main Methods:
- Analysis of RASSF2 and RASSF5A promoter methylation in thyroid tumors and cell lines.
- Correlation of RASSF2 methylation status with clinicopathological features and gene expression.
- Investigation of RASSF2's interaction with MST1/MST2 and its effect on apoptosis and cell proliferation.
Main Results:
- Frequent methylation of RASSF2 and RASSF5A CpG island promoters was observed in thyroid tumors.
- RASSF2 promoter hypermethylation was significantly increased in thyroid carcinomas compared to normal tissues and benign conditions.
- RASSF2 hypermethylation correlated with age, reduced expression, and was reversed by DNA methylation inhibitors, leading to suppressed colony formation and induced apoptosis via MST1/MST2 interaction.
Conclusions:
- RASSF2 acts as a tumor suppressor gene in thyroid carcinogenesis.
- Epigenetic inactivation, specifically promoter hypermethylation, is a key mechanism for RASSF2 silencing in thyroid cancer.
- RASSF2 represents a novel, epigenetically silenced candidate tumor suppressor in the context of thyroid cancer.
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