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FLRT2 functions as Tumor Suppressor gene inactivated by promoter methylation in Colorectal Cancer
Xiaohong Guo1, Chao Song2, Lei Fang1
1Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
Abstract:
Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epigenetic alterations, especially DNA methylation, contribute to the initiation and progression of CRC. To identify novel methylated tumor suppressors in CRC, MethylRAD-Seq screening was performed. As the result, FLRT2 was found to be preferentially methylated. In the present study, we aimed to elucidate the epigenetic regulations and biological functions of FLRT2 in CRC. Significant FLRT2 hypermethylation was initially confirmed in CRC samples and cell lines. Meanwhile, downregulated expression of FLRT2 was observed in CRC, which is probably attributed to promoter methylation of FLRT2. Consistently, the expression of FLRT2 was restored after treatment with DNA demethylating agent 5-AZA. FLRT2 overexpression resulted in impaired cell viability and colony formation. Additionally, FLRT2 overexpression led to a reduction in cell migration and cell invasion. Furthermore, we also observed that FLRT2 induced cell cycle arrest. Mechanistically, these effects were associated with the downregulation of phosphor-AKT, phosphor-ERK, CDK2, Cyclin A, and MMP2, and upregulation of P21. Taken together, these results define a tumor-suppressor role of FLRT2 with epigenetic silencing in the pathogenesis of CRC. Moreover, FLRT2 promoter methylation may be a useful epigenetic biomarker for the prevention and treatment of CRC.
Insights
Epigenetic silencing of FLRT2 via DNA methylation suppresses colorectal cancer (CRC) progression. Restoring FLRT2 expression inhibits CRC cell growth, migration, and invasion, highlighting FLRT2 as a potential biomarker.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Colorectal cancer (CRC) remains a significant global health challenge, with epigenetic alterations like DNA methylation playing a crucial role in its development.
- Identifying novel tumor suppressor genes silenced by epigenetic mechanisms is vital for understanding CRC pathogenesis and developing targeted therapies.
Purpose of the Study:
- To investigate the epigenetic regulation and functional role of FLRT2 in colorectal cancer.
- To determine if FLRT2 acts as a tumor suppressor gene silenced by promoter hypermethylation in CRC.
Main Methods:
- MethylRAD-Seq screening was employed to identify methylated genes in CRC.
- FLRT2 hypermethylation and expression levels were analyzed in CRC tissues and cell lines.
- The functional impact of FLRT2 overexpression on CRC cell behavior was assessed, including viability, colony formation, migration, and invasion.
- Mechanistic studies investigated downstream signaling pathways affected by FLRT2.
Main Results:
- FLRT2 was identified as a gene preferentially methylated in CRC.
- Significant FLRT2 hypermethylation and corresponding downregulation were confirmed in CRC samples and cell lines.
- DNA demethylation treatment (5-AZA) restored FLRT2 expression.
- Overexpression of FLRT2 suppressed CRC cell viability, colony formation, migration, and invasion, inducing cell cycle arrest.
- FLRT2's tumor-suppressive effects were linked to modulation of AKT, ERK, CDK2, Cyclin A, MMP2, and P21 pathways.
Conclusions:
- FLRT2 functions as a tumor suppressor in colorectal cancer, with its silencing mediated by epigenetic promoter methylation.
- FLRT2 hypermethylation represents a potential epigenetic biomarker for CRC prevention and treatment strategies.
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