RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma.

Abstract

BACKGROUND:

Long non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation and progression of esophageal squamous cell carcinoma (ESCC). N6-methyladenosine (m6A) modification now is recognized as a master driver of RNA function to maintain homeostasis in cancer cells. However, how m6A regulates LncRNA function and its role in tumorigenesis of ESCC remain unclear.

METHODS:

Multiple ESCC datasets were used to analyze gene expression in tumor tissues and normal tissues. Kaplan-Meier method and the ROC curve were conducted to evaluate the prognostic value and diagnostic value of LINC00022 in ESCC, respectively. Both gain-of-function and loss-of-function experiments were employed to investigate the effects of LINC00022 on ESCC growth in vitro and in vivo. Bioinformatics analysis, colorimetric m6A assay, RIP, MeRIP and co-IP was performed to explore the epigenetic mechanism of LINC00022 up-regulation in ESCC.

RESULTS:

Here we report that m6A demethylation of LncRNA LINC00022 by fat mass and obesity-associated protein (FTO) promotes tumor growth of ESCC in vivo. Clinically, we revealed that LINC00022 was up-regulated in primary ESCC samples and was predictive of poor clinical outcome for ESCC patients. Mechanistically, LINC00022 directly binds to p21 protein and promotes its ubiquitination-mediated degradation, thereby facilitating cell-cycle progression and proliferation. Further, the elevated FTO in ESCC decreased m6A methylation of LINC00022 transcript, leading to the inhibition of LINC00022 decay via the m6A reader YTHDF2. Over-expression of FTO was shown to drive LINC00022-dependent cell proliferation and tumor growth of ESCC.

CONCLUSIONS:

Thus, this study demonstrated m6A-mediated epigenetic modification of LncRNA contributes to the tumorigenesis in ESCC and LINC00022, specific target of m6A, serves as a potential biomarker for this malignancy.

• Authors: Yuanbo Cui, Chunyan Zhang, Shanshan Ma, Zhe Li, Wenjie Wang, Ya Li, Yingchao Ma, Jiarui Fang, Yaping Wang, Wei Cao, Fangxia Guan
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 294 (Sep 20 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 34544449 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• RNA, Long Noncoding
• RNA, Messenger
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• FTO protein, human

Topics

• Alpha-Ketoglutarate-Dependent Dioxygenase FTO (metabolism)
• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• DNA Methylation
• Disease Models, Animal
• Epigenesis, Genetic
• Esophageal Squamous Cell Carcinoma (genetics, metabolism, mortality, pathology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Male
• Mice
• RNA, Long Noncoding (genetics)
• RNA, Messenger (genetics, metabolism)