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Theranostics 2020; 10(26):12072-12089. doi:10.7150/thno.51231 This issue Cite

Research Paper

YTHDF1-enhanced iron metabolism depends on TFRC m⁶A methylation

Jing Ye^1*, Zhanggui Wang^2*, Xiaozhen Chen³, Xiaohua Jiang¹, Zhihuai Dong¹, Sunhong Hu¹, Wenya Li¹, Yuehui Liu⁴, Bing Liao⁴, Weidong Han^5✉, Jiaying Shen^5✉, Mang Xiao^1✉

1. Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
2. Department of Radiotherapy, The Second People's Hospital of Anhui Province, Hefei, Anhui, China.
3. Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
4. Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital Of Nanchang University, Nanchang, Jiangxi, China.
5. Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Weidong Han, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, East Qingchun Road Nr.3, Hangzhou, Zhejiang, 310016, China. E-mail: hanwdedu.cn; Jiaying Shen, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, East Qingchun Road Nr.3, Hangzhou, Zhejiang, 310016, China. E-mail: 11318167edu.cn; Mang Xiao, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, East Qingchun Road Nr.3, Hangzhou, Zhejiang, 310016, China. E-mail: joelxmedu.cn. More

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 (m⁶A) modification has expanded the realm of previously undiscovered post-transcriptional gene regulation mechanisms in eukaryotes. Many studies have demonstrated that m⁶A methylation represents a distinct layer of epigenetic deregulation in carcinogenesis and tumor proliferation. However, the status of m⁶A modification and iron metabolism in HPSCC remains unknown.

Methods: Bioinformatics analysis, sample analysis, and transcriptome sequencing were performed to evaluate the correlation between m⁶A modification and iron metabolism. Iron metabolic and cell biological analyses were conducted to evaluate the effect of the m⁶A reader YTHDF1 on HPSCC proliferation and iron metabolism. Transcriptome-wide m⁶A-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 m⁶A-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 m⁶A-dependent mechanism. From a therapeutic perspective, targeting YTHDF1 and TFRC-mediated iron metabolism may be a promising strategy for HPSCC.

Keywords: Hypopharyngeal squamous cell carcinoma, N6-methyladenosine (m⁶A) modification, YTHDF1, Iron metabolism, TFRC

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