YTHDF1-enhanced iron metabolism depends on TFRC m⁶A methylation

Abstract

Background: Among head and neck squamous cell carcinomas (HNSCCs), hypopharyngeal squamous cell carcinoma (HPSCC) has the worst prognosis. Iron metabolism, which plays a crucial role in tumor progression, is mainly regulated by alterations to genes and post-transcriptional processes. The recent discovery of the N6-methyladenosine (m 6 A) modification has expanded the realm of previously undiscovered post-transcriptional gene regulation mechanisms in eukaryotes. Many studies have demonstrated that m 6 A methylation represents a distinct layer of epigenetic deregulation in carcinogenesis and tumor proliferation. However, the status of m 6 A modification and iron metabolism in HPSCC remains unknown. Methods: Bioinformatics analysis, sample analysis, and transcriptome sequencing were performed to evaluate the correlation between m 6 A modification and iron metabolism. Iron metabolic and cell biological analyses were conducted to evaluate the effect of the m 6 A reader YTHDF1 on HPSCC proliferation and iron metabolism. Transcriptome-wide m 6 A-seq and RIP-seq data were mapped to explore the molecular mechanism of YTHDF1 function in HPSCC. Results: YTHDF1 was found to be closely associated with ferritin levels and intratumoral iron concentrations in HPSCC patients at Sir Run Run Shaw Hospital. YTHDF1 induced-HPSCC tumorigenesis depends on iron metabolism in vivo in vitro . Mechanistically, YTHDF1 methyltransferase domain interacts with the 3'UTR and 5'UTR of TRFC mRNA, then further positively regulates translation of m 6 A-modified TFRC mRNA. Gain-of-function and loss-of-function analyses validated the finding showing that TFRC is a crucial target gene for YTHDF1-mediated increases in iron metabolism. Conclusion: YTHDF1 enhanced TFRC expression in HPSCC through an m 6 A-dependent mechanism. From a therapeutic perspective, targeting YTHDF1 and TFRC-mediated iron metabolism may be a promising strategy for HPSCC.

RNA m6A Demethylase ALKBH5 Protects Against Pancreatic Ductal Adenocarcinoma via Targeting Regulators of Iron Metabolism

“…It is worth to investigate whether ALKBH5-FBXL5 pathway is involved in multiple biological processes. Apart from our observation, a recent study found that YTHDF1 induced HPSCC tumorigenesis depended on iron metabolism (Ye et al, 2020). Given the significantly lower expression of YTHDF1 in the stromal cells and positive correlation with OS of patients with PDAC observed in this study, it will be interesting to determine whether stromal YTHDF1 also exerts an iron-metabolism dependent protective role in pancreatic cancer.…”

m(6)A mRNA Methylation Regulates Ferroptosis in HPSCC by Targeting NFE2L2/NRF2

“…Mechanistically, YTHDF1 enhanced transferrin receptors (TFRC) expression through an m 6 A-dependent mechanism 50 . To determine whether YTHDF1 recognized the m 6 A modi cation on NFE2L2/NRF2, we reanalyzed the sequence data, in which YTHDF1-knockdown and control FaDu cells were subjected.…”

The Biological Function, Mechanism, and Clinical Significance of m6A RNA Modifications in Head and Neck Carcinoma: A Systematic Review

“…YTHDF1 knockout was found to reduce TFRC protein expression in Detroit562 and FADU cells without affecting TFRC mRNA expression or protein stability, indicating that YTHDF1 upregulates TFRC translation via its methyltransferase domain. Moreover, high levels of YTHDF1 and TFRC have been associated with poor prognosis in patients receiving chemoradiotherapy or radiation (CCT/RT) adjuvant therapy and YTHDF1 has been shown to increase TFRC expression in HPSCC in an m6A-dependent manner ( Ye et al, 2020 ). Although no other m6A modification-related molecules have yet been associated with HPSCC, m6A is thought to play an important role and future studies should be aimed at identifying the precise roles of various m6A-related proteins in HPSCC tumors.…”