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Updated: Jul 14, 2026
LINE-1 Methylation Analysis in Mesenchymal Stem Cells Treated with Osteosarcoma-Derived Extracellular Vesicles
Published on: February 1, 2020
Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma
Claudia Seidel1, Undraga Schagdarsurengin, Karen Blümke
1AWG Tumor Genetics of the Medical Faculty, Martin-Luther-University Halle-Wittenberg, Magdeburger Strasse 2, Halle/Saale, Germany.
Abstract:
The RASSF1A tumor suppressor is involved in regulation of apoptosis and cell cycle progression. RASSF1A is localized to microtubules and binds the apoptotic kinases MST1 and MST2. It has been shown that this interaction is mediated by the Sav-RASSF-Hpo domain, which is an interaction domain characterized for the Drosophila proteins Sav (human WW45), Hpo (human MST1 and MST2) and Warts/LATS (large tumor suppressor). Previously, we have reported that RASSF1A hypermethylation occurs frequently in soft tissue sarcoma and is associated with an unfavorable prognosis for cancer patients. In our study, we performed methylation analysis of the CpG island promoter of MST1, MST2, WW45, LATS1 and LATS2 in soft tissue sarcomas by methylation-specific PCR. No or a very low methylation frequency was detected for WW45, LATS1 and LATS2 (<7%). In 19 out of 52 (37%) sarcomas, a methylated promoter of MST1 was detected and 12 out of 60 (20%) samples showed methylation of the MST2 promoter. Methylation status of MST1 was confirmed by bisulfite sequencing. In tumors harboring a methylated promoter of MST1, a reduction of MST1 expression was observed by RT-PCR. In leiomyosarcomas, MST1 and MST2 or RASSF1A methylation were mutually exclusive (P = 0.007 and P = 0.025, respectively). Surprisingly, a significantly increased risk for tumor-related death was found for patients with an unmethylated MST1 promoter (P = 0.036). In summary, our results suggest that alteration of the Sav-RASSF1-Hpo tumor suppressor pathway may occur through hypermethylation of the CpG island promoter of MST1, MST2 and/or RASSF1A in human sarcomas.
Insights
Hypermethylation of MST1 and MST2 promoters is frequent in soft tissue sarcomas, impacting tumor suppressor pathways. Unmethylated MST1 promoter correlates with increased risk of tumor-related death in sarcoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The RASSF1A tumor suppressor regulates apoptosis and cell cycle progression.
- RASSF1A interacts with apoptotic kinases MST1 and MST2 via the Sav-RASSF-Hpo domain.
- RASSF1A hypermethylation is common in soft tissue sarcomas and linked to poor prognosis.
Purpose of the Study:
- To investigate the methylation status of key genes in the Sav-RASSF-Hpo pathway in soft tissue sarcomas.
- To determine the correlation between promoter methylation and gene expression and patient outcomes.
Main Methods:
- Methylation-specific PCR was used to analyze CpG island promoter methylation of MST1, MST2, WW45, LATS1, and LATS2 in soft tissue sarcomas.
- Bisulfite sequencing confirmed MST1 methylation status.
- RT-PCR assessed MST1 expression levels.
Main Results:
- WW45, LATS1, and LATS2 showed low methylation frequencies (<7%).
- MST1 promoter methylation was detected in 37% of sarcomas, and MST2 promoter methylation in 20%.
- MST1 promoter methylation correlated with reduced MST1 expression.
- In leiomyosarcomas, MST1/MST2 or RASSF1A methylation were mutually exclusive.
- An unmethylated MST1 promoter was associated with an increased risk of tumor-related death (P=0.036).
Conclusions:
- Alterations in the Sav-RASSF1-Hpo tumor suppressor pathway in human sarcomas can occur via hypermethylation of MST1, MST2, and/or RASSF1A promoters.
- MST1 promoter methylation is a potential prognostic marker in soft tissue sarcomas.
