J Cancer 2020; 11(24):7329-7338. doi:10.7150/jca.47558

Research Paper

FLRT2 functions as Tumor Suppressor gene inactivated by promoter methylation in Colorectal Cancer

Xiaohong Guo1*, Chao Song2*, Lei Fang1, Min Li1, Longtao Yue1, Qing Sun1✉

1. Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
2. Department of Pathology, Zibo Central Hospital, Zibo, Shandong, China.
*These authors contributed equally to this study.

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Citation:
Guo X, Song C, Fang L, Li M, Yue L, Sun Q. FLRT2 functions as Tumor Suppressor gene inactivated by promoter methylation in Colorectal Cancer. J Cancer 2020; 11(24):7329-7338. doi:10.7150/jca.47558. Available from https://www.jcancer.org/v11p7329.htm

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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.

Keywords: FLRT2, DNA methylation, colorectal cancer, tumor suppressor