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CMAHP promotes metastasis by reducing ubiquitination of Snail and inducing angiogenesis via GM-CSF overexpression in gastric cancer

Oncogene volume 41, pages 159–172 (2022)Cite this article

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Abstract

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.

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Fig. 1: High CMAHP expression is correlated with poor survival in GC patients.
Fig. 2: CMAHP is involved in EMT and angiogenesis based on GSEA and MetaCore analyses.
Fig. 3: CMAHP promotes cell migration, invasion, and angiogenesis in vitro.
Fig. 4: CMAHP regulates Snail and Vimentin expression and induces GM-CSF to promote angiogenesis.
Fig. 5: CMAHP regulates RelA and c-Jun expression.
Fig. 6: GM-CSF transcriptional activity is enhanced by the CMAHP/c-Jun axis.
Fig. 7: Snail protein stability is regulated by CMAHP/RelA signaling.
Fig. 8: CMAHP promotes metastasis and angiogenesis in vivo.

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Funding

This research was funded by grants from Chang Gung Memorial Hospital, Taoyuan, Taiwan (CMRPD1H0631, CMRPD1H0632, CMRPD1H0633 to KHL; CMRPG6K0031, CMRPG6K0032, CMRPG6K0033 to CCC, and CSW) and from the Ministry of Science and Technology of the Republic of China (MOST 106-2314-B-182A-130- to CSW). And The APC was funded by Chang Gung Memorial Hospital, Taoyuan, Taiwan.

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Authors and Affiliations

  1. Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Hsiang-Wei Huang, Ching-Ying Chen & Kwang-Huei Lin

  2. Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Hsiang-Wei Huang, Ching-Ying Chen & Kwang-Huei Lin

  3. Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

    Ya-Hui Huang, Chau-Ting Yeh & Kwang-Huei Lin

  4. Department of General Surgery, Chang Gung Memorial Hospital at Chia-yi, Chia-yi, Taiwan

    Chia-Siu Wang & Cheng-Chih Chang

  5. Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan

    Kwang-Huei Lin

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Conceptualization, HWH and KHL; Investigation, HWH; Technique support, CYC and YHH, writing—original draft preparation, HWH, and KHL; Writing—review and editing, KHL; Visualization, supervision, CSW; CCC, CTY and KHL; Funding acquisition, CSW, CCC, and KHL.

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Correspondence to Kwang-Huei Lin.

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The authors declare no competing interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the paper, or in the decision to publish the results.

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Huang, HW., Chen, CY., Huang, YH. et al. CMAHP promotes metastasis by reducing ubiquitination of Snail and inducing angiogenesis via GM-CSF overexpression in gastric cancer. Oncogene 41, 159–172 (2022). https://doi.org/10.1038/s41388-021-02087-8

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