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.

LncRNA FOXP4-AS1 Promotes the Progression of Esophageal Squamous Cell Carcinoma by Interacting With MLL2/H3K4me3 to Upregulate FOXP4

“…Cytoplasmic lncRNAs can competitively bind miRNAs and regulate miRNA target genes at the posttranscriptional level (8). A large amount of literature has shown that lncRNAs play a regulatory role in the development of ESCC (9)(10)(11). In this study, the differentially expressed lncRNA FOXP4-AS1 was screened by the microarrays.…”

Comprehensive Analysis of YTHDF1 Immune Infiltrates and ceRNA in Human Esophageal Carcinoma

“…GGI network analysis discovered that YTHDF1 was closely associated with YTHDF3 and YTHDF2, which may be because their biological functions are similar and are mainly used to identify the information of m6A methylation in the cytoplasm ( Liu et al, 2020a ; Xu et al, 2021 ). Cui et al found that the increase of FTO in esophageal squamous cell carcinoma (ESCC) inhibited the decay of LINC00022 through m6A reader YTHDF2, thus, promoting cell cycle progression and proliferation ( Cui et al, 2021 ). However, there is no report on the mechanism of YTHDF1 and YTHDF3 promoting ESCA.…”

Insight into the structure, physiological function, and role in cancer of m6A readers—YTH domain-containing proteins

“…DC1 enhances the self-renewal of leukemia stem cells (LSCs) through regulating MCM4, which is the critical regulator of DNA replication [ 114 ]. In LUAD, the overexpression of DC2 regulates CYLD/NF-κB signaling pathway and inhibits the proliferation of lung cancer cells [ 115 ].…”