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

被引：17

作者：

Zhan, Ying ^{[1
]}

Qiao, Wei ^{[1
]}

Yi, Bolong ^{[2
,3
,4
]}

Yang, Xinyu ^{[2
,3
,4
]}

Li, Miaomiao ^{[2
,3
,4
]}

Sun, Lu ^{[1
]}

Ji, Lian ^{[5
]}

Su, Peng ^{[5
]}

Wang, Xin ^{[1
]}

Zhang, Furong ^{[2
,3
,4
]}

Zhang, Rui ^{[2
,3
,4
]}

Gao, Mingjun ^{[2
,3
,4
]}

Zhao, Wujun ^{[2
,3
,4
]}

Song, Yichen ^{[2
,3
,4
]}

机构：

[1] China Med Univ, Dept Ultrasound, Shengjing Hosp, Shenyang 110004, Peoples R China

[2] China Med Univ, Dept Neurosurg, Shengjing Hosp, Shenyang 110004, Peoples R China

[3] Liaoning Clin Med Res Ctr Nervous Syst Dis, Shenyang 110004, Peoples R China

[4] Key Lab Neurooncol Liaoning Prov, Shenyang 110004, Peoples R China

[5] China Med Univ, Med Res Ctr, Liaoning Key Lab Res & Applicat Anim Models Envir, Shengjing Hosp, Shenyang 110004, Peoples R China

来源：

ONCOGENE | 2022年 / 41卷 / 40期

关键词：

ATP CITRATE LYASE; TUMOR PROGRESSION; PROLIFERATION; DIFFERENTIATION; ACTIVATION; MIGRATION; INVASION;

D O I：

10.1038/s41388-022-02445-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4512 / 4523

页数：12

共 44 条

[1] Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas [J].

Beckner, Marie E. ;

Fellows-Mayle, Wendy ;

Zhang, Zhe ;

Agostino, Naomi R. ;

Kant, Jeffrey A. ;

Day, Billy W. ;

Pollack, Ian F. .

INTERNATIONAL JOURNAL OF CANCER, 2010, 126 (10) :2282-2295

[2] Multidimensional communication in the microenvirons of glioblastoma [J].

Broekman, Marike L. ;

Maas, Sybren L. N. ;

Abels, Erik R. ;

Mempel, Thorsten R. ;

Krichevsky, Anna M. ;

Breakefield, Xandra O. .

NATURE REVIEWS NEUROLOGY, 2018, 14 (08) :482-495

[3] Re-recognition of pseudogenes: From molecular to clinical applications [J].

Chen, Xu ;

Wan, Lin ;

Wang, Wei ;

Xi, Wen-Jin ;

Yang, An-Gang ;

Wang, Tao .

THERANOSTICS, 2020, 10 (04) :1479-1499

[4] Exosomal noncoding RNAs in Glioma: biological functions and potential clinical applications [J].

Cheng, Jian ;

Meng, Jinli ;

Zhu, Lei ;

Peng, Yong .

MOLECULAR CANCER, 2020, 19 (01)

[5] An Adult Drosophila Glioma Model for Studying Pathometabolic Pathways of Gliomagenesis [J].

Chi, Kuan-Cheng ;

Tsai, Wen-Chivan ;

Wu, Chia-Lin ;

Lin, Tzu-Yang ;

Hueng, Dueng-Yuan .

MOLECULAR NEUROBIOLOGY, 2019, 56 (06) :4589-4599

[6] Cellular Fatty Acid Metabolism and Cancer [J].

Currie, Erin ;

Schulze, Almut ;

Zechner, Rudolf ;

Walther, Tobias C. ;

Farese, Robert V., Jr. .

CELL METABOLISM, 2013, 18 (02) :153-161

[7] Glioma glycolipid metabolism: MSI2-SNORD12B-FIP1L1-ZBTB4 feedback loop as a potential treatment target [J].

Dong, Weiwei ;

Liu, Xiaobai ;

Yang, Chunqing ;

Wang, Di ;

Xue, Yixue ;

Ruan, Xuelei ;

Zhang, Mengyang ;

Song, Jian ;

Cai, Heng ;

Zheng, Jian ;

Liu, Yunhui .

CLINICAL AND TRANSLATIONAL MEDICINE, 2021, 11 (05)

[8] Inhibition of SOAT1 Suppresses Glioblastoma Growth via Blocking SREBP-1-Mediated Lipogenesis [J].

Geng, Feng ;

Cheng, Xiang ;

Wu, Xiaoning ;

Yoo, Ji Young ;

Cheng, Chunming ;

Guo, Jeffrey Yunhua ;

Mo, Xiaokui ;

Ru, Peng ;

Hurwitz, Brian ;

Kim, Sung-Hak ;

Otero, Jose ;

Puduvalli, Vinay ;

Lefai, Etienne ;

Ma, Jianjie ;

Nakano, Ichiro ;

Horbinski, Craig ;

Kaur, Balveen ;

Chakravarti, Arnab ;

Guo, Deliang .

CLINICAL CANCER RESEARCH, 2016, 22 (21) :5337-5348

[9] Glioma Stem Cell-Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling [J].

Gimple, Ryan C. ;

Kidwell, Reilly L. ;

Kim, Leo J. Y. ;

Sun, Tengqian ;

Gromovsky, Anthony D. ;

Wu, Qiulian ;

Wolf, Megan ;

Lv, Deguan ;

Bhargava, Shruti ;

Jiang, Li ;

Prager, Briana C. ;

Wang, Xiuxing ;

Ye, Qing ;

Zhu, Zhe ;

Zhang, Guoxin ;

Dong, Zhen ;

Zhao, Linjie ;

Lee, Derrick ;

Bi, Junfeng ;

Sloan, Andrew E. ;

Mischel, Paul S. ;

Brown, J. Mark ;

Cang, Hu ;

Huan, Tao ;

Mack, Stephen C. ;

Xie, Qi ;

Rich, Jeremy N. .

CANCER DISCOVERY, 2019, 9 (09) :1248-1267

[10] Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways [J].

Guo, Xiaofan ;

Qiu, Wei ;

Liu, Qinglin ;

Qian, Mingyu ;

Wang, Shaobo ;

Zhang, Zongpu ;

Gao, Xiao ;

Chen, Zihang ;

Xue, Hao ;

Li, Gang .

ONCOGENE, 2018, 37 (31) :4239-4259

← 1 2 3 4 5 →