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.

m6A methyltransferase KIAA1429 acts as an oncogenic factor in colorectal cancer by regulating SIRT1 in an m6A-dependent manner

“…In addition, METTL3 is reported to maintain SOX2 expression in an m 6 A-dependent mechanism to facilitate the progression of colorectal adenocarcinoma [ 28 ]. m 6 A mRNA methylation of DEGS2, a key ceramide-synthesizing enzyme, regulates the Cer metabolism to control cell proliferation in colorectal cancer [ 29 ]. Furthermore, FTO functioned as a tumor suppressor in colorectal cancer by inhibiting metastasis-associated protein 1 (MTA1) expression in an m 6 A-dependent manner [ 30 ].…”

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…Therefore, among the several factors closely associated with tumor progression, one important feature of tumor energy metabolism is amino acid degradation [ 87 ]. For example, m 6 A modification-mediated upregulation of DEGS2 in kidney cancer inhibits ceramide synthesis to increase the invasive ability of cancer cells [ 88 ]…”

Interplay Between m6A RNA Methylation and Regulation of Metabolism in Cancer

“…Regarding the molecular mechanism, Guo and collaborators found that METTL3 depletion promoted the DEGS2 mRNA, increased DEGS2 expression in HCT116 cells, suggesting that METTL3 is essential for the stability and translation of DEGS2. YTHDF2 knockdown induced the level of DEGS2 mRNA expression, meaning that YTHDF2 contributes to the DEGS2 mRNA decay (Guo et al, 2021). Collectively, this recent evidence suggests that m 6 A regulates lipid metabolism in cancer.…”

“…Among this class of lipid, delta 4 desaturase sphingolipid 2 (DEGS2) catalyzes the conversion of dhCers to phytoceramides (Casasampere et al, 2016). Recently, Guo and collaborators found the role of m 6 A modification on DEGS2 in colorectal cancer and suggested that inhibited m 6 A promotes DEGS2 expression and dysregulated lipid metabolites, contributing to colorectal cancer (Guo et al, 2021). Furthermore, overexpression of DEGS2 promoted cell growth, while depletion of DEGS2 inhibited cell growth (Casasampere et al, 2016).…”