m(6)A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1.
m(6)A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1.
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m(6)A Reader HNRNPA2B1 通过上调 ACLY 和 ACC1 促进食管癌进展。
DOI：
10.3389/fonc.2020.553045
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发表时间：
2020
影响因子：
4.7
通讯作者：
Zou X
中科院分区：
文献类型：
--
作者：
Guo H;Wang B;Xu K;Nie L;Fu Y;Wang Z;Wang Q;Wang S;Zou X
N6-甲基腺苷（m6 A）修饰是真核生物RNA上最丰富的修饰。近年来，大量的研究报道m6 A修饰和m6 A RNA甲基化调控因子参与了肿瘤的发生发展。然而，食管癌（ESCA）中的m6 A水平及其调节因子仍然知之甚少。在这项研究中，我们使用癌症基因组图谱数据分析了m6 A调节因子的表达，发现19个m6 A调节因子中有14个在ESCA样本中显著增加。然后我们进行了单变量考克斯回归分析和LASSO（最小绝对收缩和选择算子）考克斯回归模型来研究m6 A调节因子在ESCA中的预后作用，结果表明包括ALKBH 5和HNRNPA 2B 1的双基因预后标记可以预测ESCA患者的总生存期。HNRNPA 2B 1在ESCA高危亚型中表达较高，提示HNRNPA 2B 1可能参与ESCA的发生发展。随后，我们证实了m6 A和HNRNPA 2B 1的水平在ESCA中显著增加。HNRNPA 2B 1的表达与ESCA的肿瘤直径和淋巴结转移呈正相关。此外，功能研究表明，HNRNPA 2B 1的敲低抑制ESCA的增殖，迁移和侵袭。从机制上讲，我们发现HNRNPA 2B 1的敲低抑制了从头脂肪酸合成酶ACLY和ACC 1的表达，随后抑制了细胞脂质积累。总之，我们的研究为理解m6 A及其调控因子在ESCA中的作用提供了重要线索。此外，HNRNPA 2B 1作为致癌因子通过上调脂肪酸合成酶ACLY和ACC 1促进ESCA进展，其可能是人类ESCA的有希望的预后生物标志物和治疗靶点。
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.
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