Long non-coding RNAs (lncRNAs) are important epigenetic regulators, which play critical roles in diverse physiological and pathological processes. However, the regulatory mechanism of lncRNAs in lung carcinogenesis remains elusive. Here, we characterized a novel oncogenic lncRNA, designated as Lung Cancer Associated Transcript 3 (LCAT3). We predicted and validated LCAT3 by analyzing RNA-sequencing (RNA-seq) data of lung cancer tissues from TCGA. Methylated RNA immunoprecipitation was performed to assess m6A modification on LCAT3. The LCAT3-FUBP1-MYC axis was assessed by dual-luciferase reporter, RNA immunoprecipitation and Chromatin immunoprecipitation assays. Signaling pathways altered by LCAT3 knockdown were identified using RNA-seq. Furthermore, the mechanism of LCAT3 was investigated using loss-of-function and gain-of-function assays in vivo and in vitro. LCAT3 was found to be up-regulated in lung adenocarcinomas (LUAD), and its over-expression was associated with the poor prognosis of LUAD patients. LCAT3 upregulation is attributable to N6-methyladenosine (m6A) modification mediated by methyltransferase like 3 (METTL3), leading to LCAT3 stabilization. Biologically, loss-of-function assays revealed that LCAT3 knockdown significantly suppressed lung cancer cell proliferation, migration and invasion in vitro, and inhibited tumor growth and metastasis in vivo. LCAT3 knockdown induced cell cycle arrest at the G1 phase. Mechanistically, LCAT3 recruited Far Upstream Element Binding Protein 1 (FUBP1) to the MYC far-upstream element (FUSE) sequence, thereby activating MYC transcription to promote proliferation, survival, invasion and metastasis of lung cancer cells. Taken together, we identified and characterized LCAT3 as a novel oncogenic lncRNA in the lung, and validated the LCAT3-FUBP1-MYC axis as a potential therapeutic target for LUAD.

中文翻译：

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LCAT3 是一种新型 m6A 调节的长非编码 RNA，通过与 FUBP1 结合激活 c-MYC 在肺癌中发挥致癌作用


长链非编码RNA（lncRNA）是重要的表观遗传调节因子，在多种生理和病理过程中发挥着关键作用。然而，lncRNA在肺癌发生中的调控机制仍不清楚。在这里，我们表征了一种新型致癌 lncRNA，命名为肺癌相关转录本 3 (LCAT3)。我们通过分析 TCGA 中肺癌组织的 RNA 测序 (RNA-seq) 数据来预测和验证 LCAT3。进行甲基化 RNA 免疫沉淀以评估 LCAT3 上的 m6A 修饰。通过双荧光素酶报告基因、RNA 免疫沉淀和染色质免疫沉淀测定来评估 LCAT3-FUBP1-MYC 轴。使用 RNA-seq 鉴定了因 LCAT3 敲低而改变的信号通路。此外，利用体内和体外功能丧失和功能获得测定研究了 LCAT3 的机制。 LCAT3被发现在肺腺癌（LUAD）中表达上调，其过度表达与LUAD患者的不良预后相关。 LCAT3 上调可归因于甲基转移酶样 3 (METTL3) 介导的 N6-甲基腺苷 (m6A) 修饰，从而导致 LCAT3 稳定。生物学上，功能丧失测定表明，LCAT3敲低可显着抑制体外肺癌细胞的增殖、迁移和侵袭，并抑制体内肿瘤的生长和转移。 LCAT3 敲低诱导细胞周期停滞在 G1 期。从机制上讲，LCAT3将远上游元件结合蛋白1（FUBP1）招募到MYC远上游元件（FUSE）序列，从而激活MYC转录，促进肺癌细胞的增殖、存活、侵袭和转移。 综上所述，我们鉴定并表征了 LCAT3 作为肺部的一种新型致癌 lncRNA，并验证了 LCAT3-FUBP1-MYC 轴作为 LUAD 的潜在治疗靶点。