Abstract
N6-methyladenosine (m6A) modification is the most abundant modification on eukaryotic RNA. In recent years, lots of studies have reported that m6A modification and m6A RNA methylation regulators were involved in cancer progression. However, the m6A level and its regulators in esophageal cancer (ESCA) remain poorly understood. In this study, we analyzed the expression of m6A regulators using The Cancer Genome Atlas data and found 14 of 19 m6A regulators are significantly increased in ESCA samples. Then we performed a univariate Cox regression analysis and LASSO (least absolute shrinkage and selection operator) Cox regression model to investigate the prognostic role of m6A regulators in ESCA, and the results indicated that a two-gene prognostic signature including ALKBH5 and HNRNPA2B1 could predict overall survival of ESCA patients. Moreover, HNRNPA2B1 is higher expressed in high-risk scores subtype of ESCA, indicating that HNRNPA2B1 may be involved in ESCA development. Subsequently, we confirmed that the level of m6A and HNRNPA2B1 was significantly increased in ESCA. We also found that HNRNPA2B1 expression positively correlated with tumor diameter and lymphatic metastasis of ESCA. Moreover, functional study showed that knockdown of HNRNPA2B1 inhibited the proliferation, migration, and invasion of ESCA. Mechanistically, we found that knockdown of HNRNPA2B1 inhibited the expression of de novo fatty acid synthetic enzymes, ACLY and ACC1, and subsequently suppressed cellular lipid accumulation. In conclusion, our study provides critical clues to understand the role of m6A and its regulators in ESCA. Moreover, HNRNPA2B1 functions as an oncogenic factor in promoting ESCA progression via up-regulation of fatty acid synthesis enzymes ACLY and ACC1, and it may be a promising prognostic biomarker and therapeutic target for human ESCA.
Highlights
Esophageal cancer (ESCA) is one of the major malignant cancers that threatened human health worldwide [1, 2]
We found that 14 of 19 m6A-related genes were significantly increased in esophageal cancer (ESCA) tissues compared with the normal tissues through heatmap visualization (Figure 1B)
The expression levels of five writers (METTL16, WT1 associated protein (WTAP), methyltransferase-like 3 (METTL3), KIAA1429, and RNA binding motif protein 15 (RBM15)) and nine readers (YTHDF1/2/3, YTHDC1, IGF2BP1/2/3, heterogeneous nuclear ribonucleoprotein C. overall survival (OS) (HNRNPC), and HNRNPA2B1) were significantly up-regulated in ESCA tissues, whereas no significant difference was found for the two erasers (FTO and alkB homolog 5 (ALKBH5)) (Figure 1C)
Summary
Esophageal cancer (ESCA) is one of the major malignant cancers that threatened human health worldwide [1, 2]. Identifying novel biomarkers and therapeutic targets for ESCA patients is an urgent need. It is well-known that lots of chemical modifications on human RNA were involved in the development of human diseases, including cancer [6, 7]. Lots of studies have shown that the writers, erasers, and readers are closely associated with the characteristics of cancer, including tumor proliferation, apoptosis, metastasis, angiogenesis, drug resistance, energy metabolism, and cancer stem cell [6, 8, 13,14,15,16]. Despite the function of m6A modification and its regulators in different malignant cancers have been reported, its role in ESCA has not been studied so far
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