Abstract
BackgroundLong 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.MethodsMultiple 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.ResultsHere 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.ConclusionsThus, 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.
Highlights
Long non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation and progression of esophageal squamous cell carcinoma (ESCC)
LINC00022 is highly expressed in ESCC and predicts poor prognosis To identify potential oncogenic LncRNAs in ESCC, we analyzed the differential expression profiles of LncRNAs (DELncRNAs) from two independent ESCC cohorts, GSE75241 and The Cancer Genome Atlas (TCGA)-ESCC
When interrogating two additional ESCC datasets from GEPIA (Fig. 1B-b, p = 1.06E-43) and CRN (Fig. 1B-c, p = 6.41E-9) databases, we found that LINC00022 was consistently increased in tumor tissues compared to normal tissues
Summary
Long non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation and progression of esophageal squamous cell carcinoma (ESCC). The 5-year survival rate for patients with advanced ESCA remains dismal, due to uncontrolled tumor growth and relapse and unknown molecular mechanisms [6,7,8]. In the past few decades, considerable efforts have been made to investigate the molecular mechanisms underlying ESCC pathogenesis [9, 10]. Both genetic, including mutations in tumor suppressor genes such as TP53 and NFE2L2 [11, 12], and epigenetic alterations, including DNA methylation and non-coding RNAs [13,14,15], have been uncovered to play pivotal roles in the tumorigenesis and development of ESCC. The understanding of oncogenesis of ESCC remains elusive, limiting the effective drug development for targeted therapy
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