Gene expression profiles of LS180 cells in which MYU, CTNNB1, or MYC expression was suppressed.

Aberrant activation of Wnt beta-catenin signalling is a major driving force in colon cancer. Wnt beta-catenin signalling induces the expression of the transcription factor c-Myc, leading to cell proliferation and tumourigenesis. c-Myc regulates multiple biological processes through its ability to directly modulate gene expression. However, the mechanisms underlying c-Myc-induced oncogenesis remain to be established. Here we identify a novel direct target of c-Myc, MYU (c-Myc-upregulated long non-coding RNA) and show that MYU is upregulated in most colon cancers and is required for the tumourigenicity of colon cancer cells. We further demonstrate that MYU associates with the RNA-binding protein hnRNP-K to stabilize CDK6 expression, and thereby promotes the G1-S transition of the cell cycle. These results suggest that the MYU/hnRNP-K/CDK6 pathway functions downstream of Wnt/c-Myc signalling and plays a critical role in the proliferation and tumourigenicity of colon cancer cells. MYU might be a promising molecular target for the therapeutic treatment of c-Myc-driven cancers. LS180 cells were transfected with a siRNA targeting MYU, CTNNB1, or MYC.

Wnt/β-连环蛋白信号通路（Wnt beta-catenin signalling）的异常激活是结直肠癌的主要驱动因素。该通路可诱导转录因子c-Myc的表达，进而介导细胞增殖与肿瘤发生。c-Myc可通过直接调控基因表达的能力，参与调控多种生物学过程。然而，c-Myc介导的肿瘤发生背后的分子机制仍有待阐明。本研究鉴定出c-Myc的全新直接靶标MYU（c-Myc上调长链非编码RNA，long non-coding RNA），并证实MYU在多数结直肠癌中呈高表达，且对结直肠癌细胞的致瘤性不可或缺。本研究进一步证实，MYU可与RNA结合蛋白异质性核核糖核蛋白K（hnRNP-K）结合，稳定细胞周期蛋白依赖性激酶6（CDK6）的表达，从而促进细胞周期的G1/S期转换。上述结果表明，MYU/hnRNP-K/CDK6通路作为Wnt/c-Myc信号通路的下游分支，在结直肠癌细胞的增殖与致瘤过程中发挥关键作用。MYU有望成为靶向c-Myc驱动型癌症的极具潜力的分子治疗靶点。本研究将靶向MYU、CTNNB1或MYC的小干扰RNA（siRNA）转染至LS180细胞中。