A Novel Microprotein, MUCP1, Mediates Succinate Transport and Promotes Colorectal Cancer Progression by Modulating Glutamine Metabolism

Metabolic reprogramming is a hallmark of colorectal cancer (CRC) progression, yet the molecular mechanisms governing this process remain largely unresolved. And the translational roles of numerous long non-coding RNAs (lncRNAs) have been largely overlooked, despite their protein products being essential in cancer progression. This study identifies MUCP1, the microprotein encoded by lncRNA MUC20-OT1, as a central regulator of metabolic processes in CRC. Positioned on the mitochondrial outer membrane, MUCP1 is vital for the export of succinate, a key oncometabolite. Acute depletion of MUCP1 causes succinate accumulation, Tricarboxylic acid cycle (TCA) instability, and disruptions in glutamine metabolism. Cancer cells lacking MUCP1 show decreased H3K4me3 modifications on genes crucial for glutamine metabolism, driving further metabolic imbalance. Sustained MUCP1 deficiency ultimately triggers metabolic reprogramming, emphasizing the role of this microprotein in linking mitochondrial metabolism to epigenetic regulation and presenting it as a promising therapeutic target in CRC. Overall design: This RNA-seq dataset examines the transcriptomic impact of MUCP1 overexpression in SW480 colorectal cancer cells. The experiment includes two groups: control (LV-NC) and MUCP1-FLAG overexpression. RNA was extracted from biological replicates of both groups for sequencing, with the aim of identifying differentially expressed genes influenced by elevated MUCP1 levels. Comparative gene expression analysis and pathway enrichment studies were conducted to assess changes, particularly in metabolic and signaling pathways.

代谢重编程是结直肠癌（colorectal cancer, CRC）进展的标志性特征，但调控该过程的分子机制目前仍未完全解析。尽管众多长链非编码RNA（long non-coding RNAs, lncRNAs）编码的蛋白质产物在癌症进展中发挥关键作用，但这类RNA的翻译功能长期以来被大幅忽视。本研究鉴定出由长链非编码RNA MUC20-OT1编码的微蛋白MUCP1，是结直肠癌代谢过程的核心调控因子。MUCP1定位于线粒体外膜，对关键癌代谢物琥珀酸的输出至关重要。急性敲低MUCP1会导致琥珀酸蓄积、三羧酸循环（tricarboxylic acid cycle, TCA）紊乱以及谷氨酰胺代谢失衡。缺失MUCP1的癌细胞中，谷氨酰胺代谢关键基因的H3K4me3修饰水平显著降低，进一步加剧代谢失衡。持续缺失MUCP1最终会诱发代谢重编程，凸显了该微蛋白在线粒体代谢与表观遗传调控之间的桥梁作用，并表明其可作为结直肠癌潜在的治疗靶点。

实验设计：本RNA测序（RNA-seq）数据集旨在探究过表达MUCP1对SW480结直肠癌细胞转录组的影响。实验设置两组：对照组（LV-NC）与MUCP1-FLAG过表达组。提取两组生物学重复样本的RNA进行测序，旨在鉴定由MUCP1水平升高所调控的差异表达基因。通过比较基因表达分析与通路富集分析，评估两组间的基因表达变化，尤其是代谢通路与信号通路的改变。