Work

m6A-induced DEAD-box RNA helicase 21 enhances lipid metabolism via 3‑hydroxy-3-methylglutaryl-CoA synthases 1 in colorectal cancer

Year: 2025

Type: article

Abstract: BACKGROUND: Altered lipid metabolism is a well-known hallmark of cancer. However, the underlying mechanisms of altered lipid metabolism in colorectal cancer (CRC) progression requires further investigation. Previously we have revealed that DEAD-box RNA helicase 21 (DDX21) promotes CRC metastasis via liquid-liquid phase separation. In this study, we identify DDX21 as a novel regulator of lipid metabolism in CRC. METHODS: In vitro and in vivo assays illustrated the biological role of DDX21 and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) in CRC lipid metabolism and progression. Bioinformatics analysis, ChIP, meRIP, RIP, RNA stability assay and dual-luciferase reporter assay were applied to explore the underlying molecular mechanisms. The expression levels and prognostic role of YTHDF1/DDX21/HMGCS1 axis in CRC patients were analyzed by immunohistochemical staining and Kaplan-Meier plotter. RESULTS: DDX21 enhanced CRC progression via promoting lipid metabolism. Mechanistically, YTHDF1 enhanced DDX21 mRNA stability by recognizing its m6A-modified sites. DDX21 further binded to 3‑hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) promoter region and directly activated HMGCS1 transcription. Moreover, our clinical data showed that a simultaneously high expression of YTHDF1, DDX21 and HMGCS1 predicted an unfavorable overall survival in CRC patients. CONCLUSIONS: Our study demonstrates that the YTHDF1/DDX21/HMGCS1 axis promotes CRC progression via regulating lipid metabolism and DDX21 might be a promising target for CRC therapy.

Source: Translational Oncology

DOI: 10.1016/j.tranon.2025.102373