Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Oncogene. 2022 Jan;41(2):159-172. doi: 10.1038/s41388-021-02087-8. Epub 2021 Oct 29.
Pseudogenes are generally considered "junk" DNA or "genomic fossils" generated during the evolution process that lack biological activity. However, accumulating reports indicate that pseudogenes have biological functions critical for cancer development. Experiments from the current study showed marked overexpression of the cytidine monophospho-N-acetylneuraminic acid hydroxylase pseudogene (CMAHP) in gastric cancer, which was associated with poor overall survival. However, the mechanisms underlying the activity of CMAHP in tumor development are largely unknown. Gene Set Enrichment Analysis (GSEA) revealed that CMAHP-correlated genes are significantly involved in epithelial-mesenchymal transition (EMT) and angiogenesis. Functional studies further confirmed that CMAHP mediates metastasis and angiogenesis in vitro and in vivo. Furthermore, CMAHP promoted cancer cell migration, invasion, and metastasis through Snail overexpression, which decreased ubiquitination mediated by NF-κB signaling. Angiogenesis is known to be induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. CMAHP increased GM-CSF transactivation via promoting direct binding of c-Jun to the -1981/-1975 region of the GM-CSF promoter. Notably, CMAHP interacts with Histone H1.4 promoting histone acetylation to enhance c-Jun and RelA (p65) expression. Our collective findings provide novel evidence that CMAHP contributes to tumor progression and modulates metastasis and angiogenesis in gastric cancer.
假基因通常被认为是在进化过程中产生的“垃圾”DNA 或“基因组化石”，缺乏生物活性。然而，越来越多的报道表明，假基因具有对癌症发展至关重要的生物学功能。本研究的实验表明，在胃癌中，胞苷一磷酸-N-乙酰神经氨酸羟化酶假基因（CMAHP）明显过表达，与总体生存不良相关。然而，CMAHP 在肿瘤发展中的活性的机制在很大程度上是未知的。基因集富集分析（GSEA）表明，CMAHP 相关基因显著参与上皮-间充质转化（EMT）和血管生成。功能研究进一步证实，CMAHP 在体外和体内介导转移和血管生成。此外，CMAHP 通过上调 Snail 促进癌症细胞迁移、侵袭和转移，从而减少 NF-κB 信号介导的泛素化。众所周知，粒细胞-巨噬细胞集落刺激因子（GM-CSF）刺激可诱导血管生成。CMAHP 通过促进 c-Jun 与 GM-CSF 启动子的-1981/-1975 区域的直接结合，增加 GM-CSF 的反式激活。值得注意的是，CMAHP 与组蛋白 H1.4 相互作用，促进组蛋白乙酰化，从而增强 c-Jun 和 RelA（p65）的表达。我们的综合研究结果提供了新的证据，表明 CMAHP 有助于肿瘤进展，并调节胃癌中的转移和血管生成。
