M6A methylation of DEGS2, a key ceramide-synthesizing enzyme, is involved in colorectal cancer progression through ceramide synthesis.

Abstract

N6-methyladenosine (m6A) is the most prevalent RNA epigenetic regulator in cancer. However, the understanding of m6A modification on lipid metabolism regulation in colorectal cancer (CRC) is very limited. Here, we observed that human CRCs exhibited increased m6A mRNA methylation mediated by dysregulation of m6A erasers and readers. By performing methylated RNA-immunoprecipitation sequencing (MeRIP-seq) and transcriptomic sequencing (RNA-seq), we identified DEGS2 as a downstream target of m6A dysregulation. Overexpression or knockdown of DEGS2 confirmed the role of DEGS2 in proliferation, invasion and metastasis of CRC both in vitro and in vivo. Mechanistic studies identified the specific m6A modification site within DEGS2 mRNA, and mutation of this target site was found to drastically enhance the proliferative and invasive ability of CRC cells in vitro and promote tumorigenicity in vivo. Lipidome analysis showed that lipid metabolism was dysregulated in CRC. Moreover, ceramide synthesis was suppressed due to DEGS2 upregulation mediated by m6A modification in CRC tissues. Our findings highlight that the function of DEGS2 m6A methylation in CRC and extend the understanding of the importance of RNA epigenetics in cancer biology.

• Authors: Wei Guo, Cuiyu Zhang, Panpan Feng, Mingying Li, Xia Wang, Yuan Xia, Dawei Chen, Jingxin Li
• Journal: Oncogene (Oncogene) Vol. 40 Issue 40 Pg. 5913-5924 (10 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34363020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Ceramides
• Gpm6a protein, mouse
• Membrane Glycoproteins
• Nerve Tissue Proteins

Topics

• Ceramides (metabolism)
• Colorectal Neoplasms (genetics)
• Disease Progression
• Humans
• Membrane Glycoproteins (metabolism)
• Methylation
• Nerve Tissue Proteins (metabolism)