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Dual role of pseudogene TMEM198B in promoting lipid metabolism and immune escape of glioma cells

Oncogene volume 41, pages 4512–4523 (2022)Cite this article

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Abstract

Dysregulation of pseudogenes, enhancement of fatty acid synthesis and formation of immunosuppressive microenvironment are important factors that promote the malignant progression of glioma. It is of great significance to search for the molecular mechanism of interaction between the three and then perform targeted interference for improving the treatment of glioma. In this study, we found that pseudogene transmembrane protein 198B (TMEM198B) was highly expressed in glioma tissues and cell lines, and it could promote malignant progression of glioma by regulating lipid metabolism reprogramming and remodeling immune microenvironment. Applying the experimental methods of gene interference, lipidomics and immunology, we further confirmed that TMEM198B promoted PLAG1 like zinc finger 2 (PLAGL2) expression by mediating tri-methylation of histone H3 on lysine 4 (H3K4me3) of PLAGL2 through binding to SET domain containing 1B (SETD1B). Increased PLAGL2 could transcriptional activate ATP citrate lyase (ACLY) and ELOVL fatty acid elongase 6 (ELOVL6) expression, and then influenced the biological behaviors of glioma cells via enhancing the de novo lipogenesis and fatty acid acyl chain elongation. At the same time, TMEM198B promoted macrophages lipid accumulation and intensification of fatty acid oxidation (FAO) through glioma-derived exosomes (GDEs), further induced macrophages to M2 polarization, which subsequently facilitated immune escape of glioma cells. In conclusion, our present study clarifies that the TMEM198B/PLAGL2/ACLY/ELOVL6 pathway conducts crucial regulatory effects on the malignant progression of glioma, which provides novel targets and new ideas for molecular targeted therapy and immunotherapy of glioma.

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Fig. 1: TMEM198B exerts carcinogenic role in glioma cells via upregulating its downstream effector gene PLAGL2.
Fig. 2: TMEM198B regulates PLAGL2 expression by mediating H3K4me3 of PLAGL2 through binding to SETD1B.
Fig. 3: ACLY and ELOVL6 functioned as oncogenes in glioma cells, and were downstream targets of PLAGL2.
Fig. 4: TMEM198B enhanced de novo fatty acid synthesis and acyl chain elongation in glioma cells.
Fig. 5: TMEM198B regulates M2 polarization of macrophages through GDEs to promote immune escape of glioma cells.
Fig. 6: U87-shTMEM198B-exo significantly impaired M2 polarization of macrophages and tumor growth in vivo.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work is supported by grants from the Natural Science Foundation of China (81571686, 81571868 and 81372682), Natural Science Foundation of Liaoning Province (2020-MS-170) and Outstanding Scientific Research Talent Plan of Shengjing hospital (NO.2020M0322).

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Authors and Affiliations

  1. Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Ying Zhan, Wei Qiao, Lu Sun & Xin Wang

  2. Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Bolong Yi, Xinyu Yang, Miaomiao Li, Furong Zhang, Rui Zhang, Mingjun Gao, Wujun Zhao & Yichen Song

  3. Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China

    Bolong Yi, Xinyu Yang, Miaomiao Li, Furong Zhang, Rui Zhang, Mingjun Gao, Wujun Zhao & Yichen Song

  4. Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China

    Bolong Yi, Xinyu Yang, Miaomiao Li, Furong Zhang, Rui Zhang, Mingjun Gao, Wujun Zhao & Yichen Song

  5. Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Lian Ji & Peng Su

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Contributions

YS contributed to the experiment design and implementation, manuscript draft, and data analysis. YZ contributed to the experiment implementation and data analysis. WZ conceived or designed the experiments. WQ, BY, ML, LJ, PS, RZ, and LS. performed the experiments. WZ, MG, XW, FZ, and XY analyzed the data. YZ conceived or designed the experiments, performed the experiments, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yichen Song.

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Zhan, Y., Qiao, W., Yi, B. et al. Dual role of pseudogene TMEM198B in promoting lipid metabolism and immune escape of glioma cells. Oncogene 41, 4512–4523 (2022). https://doi.org/10.1038/s41388-022-02445-0

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