More than half of all cancers demonstrate aberrant c-Myc expression, making this arguably the most important human oncogene. Deregulated long non-coding RNAs (lncRNAs) are also commonly implicated in tumorigenesis, and some limited examples have been established where lncRNAs act as biological tuners of c-Myc expression and activity. Here, we demonstrate that the lncRNA denoted c-Myc Enhancing Factor (MEF) enjoys a cooperative relationship with c-Myc, both as a transcriptional target and driver of c-Myc expression. Mechanistically, MEF functions by binding to and stabilizing the expression of hnRNPK in colorectal cancer cells. The MEF-hnRNPK interaction serves to disrupt binding between hnRNPK and the E3 ubiquitin ligase TRIM25, which attenuates TRIM25-dependent hnRNPK ubiquitination and proteasomal destruction. In turn, the stabilization of hnRNPK through MEF enhances c-Myc expression by augmenting the translation c-Myc. Moreover, modulating the expression of MEF in shRNA-mediated knockdown and overexpression studies revealed that MEF expression is essential for colorectal cancer cell proliferation and survival, both in vitro and in vivo. From the clinical perspective, we show that MEF expression is differentially increased in colorectal cancer tissues compared to normal adjacent tissues. Further, correlations exist between MEF, c-Myc, and hnRNPK suggesting the MEF-c-Myc positive feedback loop is active in patients. Together these data demonstrate that MEF is a pivotal partner of the c-Myc network and propose MEF as a valuable therapeutic target for colorectal cancer.

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lncRNA MEF和c-Myc的相互调节驱动结直肠癌肿瘤发生

超过一半的癌症表现出异常的 c-Myc 表达，这使得它可以说是最重要的人类癌基因。失调的长非编码 RNA (lncRNA) 通常也与肿瘤发生有关，并且已经建立了一些有限的例子，其中 lncRNA 充当 c-Myc 表达和活性的生物调谐器。在这里，我们证明了表示为 c-Myc 增强因子 (MEF) 的 lncRNA 与 c-Myc 享有合作关系，既作为 c-Myc 表达的转录靶标，又作为 c-Myc 表达的驱动程序。从机制上讲，MEF 通过结合并稳定结直肠癌细胞中 hnRNPK 的表达来发挥作用。MEF-hnRNPK 相互作用可破坏 hnRNPK 和 E3 泛素连接酶 TRIM25 之间的结合，从而减弱 TRIM25 依赖性 hnRNPK 泛素化和蛋白酶体破坏。反过来，通过 MEF 稳定 hnRNPK 通过增强 c-Myc 翻译来增强 c-Myc 表达。此外，在 shRNA 介导的敲低和过表达研究中调节 MEF 的表达表明，MEF 表达对于结直肠癌细胞的体外和体内增殖和存活至关重要。从临床角度来看，我们发现结直肠癌组织中 MEF 表达与正常癌旁组织相比存在差异性增加。此外，MEF、c-Myc 和 hnRNPK 之间存在相关性，表明 MEF-c-Myc 正反馈环在患者体内活跃。这些数据共同证明 MEF 是 c-Myc 网络的关键合作伙伴，并提出 MEF 作为结直肠癌的有价值的治疗靶点。