POFUT1 promotes colorectal cancer development through the activation of Notch1 signaling

Yuheng Du,Xiaorong Li,Daojiang Li,Chen Su,Nanpeng Li,Miao Chen,Runliu Wu,Changwei Lin,Gui Hu,Chunxing Yang

doi:10.1038/s41419-018-1055-2

Yuheng Du, Xiaorong Li + Show 8 more

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https://doi.org/10.1038/s41419-018-1055-2

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Abstract

Copy number variations (CNVs) are key drivers of colorectal cancer (CRC). Our previous studies revealed that protein O-fucosyltransferase 1 (POFUT1) overexpression is driven by CNVs during CRC development. The potential role and underlying mechanisms of POFUT1 in CRC were not investigated. In this study, we analyzed the expression of POFUT1 in CRC from cosmic and TCGA databases and confirmed that POFUT1 is highly expressed in CRC. We used well characterized CRC cell lines, including SW620 and HCT116 to establish a model POFUT1 knockdown cell line. Using these cells, we investigated the role of POFUT1 in CRC. Our data revealed that silencing POFUT1 in CRC cells inhibits cell proliferation, decreases cell invasion and migration, arrests cell cycle progression, and stimulates CRC cell apoptosis in vitro. We further demonstrate that POFUT1 silencing dramatically suppresses CRC tumor growth and transplantation in vivo. We additionally reveal new mechanistic insights into the role of POFUT1 during CRC, through demonstrating that POFUT1 silencing inhibits Notch1 signaling. Taken together, our findings demonstrate that POFUT1 is a tumor activating gene during CRC development, which positively regulates CRC tumor progression through activating Notch1.

Highlights

Colorectal cancer (CRC) is a leading cause of cancerrelated deaths in both economically developed and developing countries[1]
The Catalogue Of Somatic Mutations In Cancer (COSMIC)[36], the world’s largest and most comprehensive resource for exploring the impact of somatic mutations in human cancer, was used to analyze the expression of protein O-fucosyltransferase 1 (POFUT1) in colorectal cancer tissues, the result found that overexpression of POFUT1 occurred in 53.44% (326/610) CRC tissues
To further confirms this conclusion, 35 matched pairs of human CRC tissue, and adjacent non-tumor tissue was selected for quantitative polymerase chain reaction and western blot analysis, the result demonstrated that POFUT1 is significantly upregulated in human CRC tissue (Fig. 1c–e), suggesting its association with CRC progression

Summary

Introduction

Colorectal cancer (CRC) is a leading cause of cancerrelated deaths in both economically developed and developing countries[1]. CRC remains one of the most important global malignancies and according to recent statistics, represents the fastest growing cancer in China[2]. It is known that CRC has a poor prognosis due to the proliferative, migratory and invasive capabilities of CRC tumors[3,4]. CRC cells can be influenced by various intrinsic and extrinsic factors, including hormones, cytokines, and oncogenes[5,6,7,8]. Our previous studies identified copy number variations (CNVs) in CRC that led to genes fucosyltransferases 1(POFUT1). The contribution of POFUT1 to CRC development was not investigated

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