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Open Access 01-12-2024 | NSCLC | Research

GABPB1 plays a cancer-promoting role in non-small cell lung cancer

Authors: Tuo Wang, Cong Cao, Yu Fan, Jialing Xu, Tao Hua, Jie Ding, Zejie Liu, Beili Wang, Juanwen Lian

Published in: Discover Oncology | Issue 1/2024

Abstract

Background

GABPB1, the gene that encodes two isoforms of the beta subunit of GABP, has been identified as an oncogene in multiple malignant tumors. However, the role and mode of action of GABPB1 in malignant tumors, especially in lung cancer, are not well understood and need further research.

Methods

Our research focused on examining the biological function of GABPB1 in NSCLC (Non-Small Cell Lung Cancer). We analysed tumor data from public databases to assess the expression of GABPB1 in NSCLC and its correlation with patient prognosis and investigated GABPB1 expression and methylation patterns in relation to the tumor microenvironment. In parallel, experiments were conducted using short hairpin RNA (shRNA) to suppress the GABPB1 gene in human lung cancer cells to evaluate the effects on cell proliferation, viability, and apoptosis.

Results

GABPB1 was widely expressed in various tissues of the human body. Compared to that in normal tissues, the expression of this gene was different in multiple tumor tissues. GABPB1 was highly expressed in lung cancer tissues and cell lines. Its expression was associated with molecular subtype and cellular signalling pathways, and a high level of GABPB1 expression was related to a poor prognosis in lung adenocarcinoma patients. The expression and methylation of GABPB1 affect the tumor microenvironment. After suppressing the expression of GABPB1 in both A549 and H1299 cells, we found a decrease in cell growth and expression, the formation of clones and an increase in the apoptosis rate.

Conclusions

Our research verified that GABPB1 promotes the tumorigenesis of NSCLC and has an inhibitory effect on tumor immunity. The specific role of GABPB1 may vary among different pathological types of NSCLC. This molecule can serve as a prognostic indicator for lung adenocarcinoma, and its methylation may represent a potential breakthrough in treatment by altering the tumor immune microenvironment in lung squamous cell carcinoma. The role and mechanism of action of GABPB1 in NSCLC should be further explored.

Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O. Influence of estrogen in non-small cell lung cancer and its clinical implications. J Thorac Dis. 2018;10:482–97. https://doi.org/10.21037/jtd.2017.12.61.CrossRefPubMedPubMedCentral

Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–8. https://doi.org/10.1056/NEJMoa011954.CrossRefPubMed

Salehi-Rad R, Li R, Paul MK, Dubinett SM, Liu B. The biology of lung cancer: development of more effective methods for prevention, diagnosis, and treatment. Clin Chest Med. 2020;41:25–38. https://doi.org/10.1016/j.ccm.2019.10.003.CrossRefPubMed

Lim ZF, Ma PC. Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy. J Hematol Oncol. 2019;12:134. https://doi.org/10.1186/s13045-019-0818-2.CrossRefPubMedPubMedCentral

Mayekar MK, Bivona TG. Current landscape of targeted therapy in lung cancer. Clin Pharmacol Ther. 2017;102:757–64. https://doi.org/10.1002/cpt.810.CrossRefPubMed

Li X, Zhou X, Li Y, et al. Activating transcription factor 3 promotes malignance of lung cancer cells in vitro. Thorac Cancer. 2017;8:181–91. https://doi.org/10.1111/1759-7714.12421.CrossRefPubMedPubMedCentral

Liu Y, Wang L, Lin XY, et al. The transcription factor DEC1 (BHLHE40/STRA13/SHARP-2) is negatively associated with TNM stage in non-small-cell lung cancer and inhibits the proliferation through cyclin D1 in A549 and BE1 cells. Tumour Biol. 2013;34:1641–50. https://doi.org/10.1007/s13277-013-0697-z.CrossRefPubMed

Nakahara Y, Hosomi Y, Saito M, et al. Predictive significance of thyroid transcription factor-1 expression in patients with non-squamous non-small cell lung cancer with wild-type epidermal growth factor receptor treated with erlotinib. Mol Clin Oncol. 2016;5:14–8. https://doi.org/10.3892/mco.2016.870.CrossRefPubMedPubMedCentral

de la Brousse FC, Birkenmeier EH, King DS, Rowe LB, McKnight SL. Molecular and genetic characterization of GABP beta. Genes Dev. 1994;8:1853–65. https://doi.org/10.1101/gad.8.15.1853.CrossRefPubMed

10.

Yu S, Jing X, Colgan JD, Zhao DM, Xue HH. Targeting tetramer-forming GABPβ isoforms impairs self-renewal of hematopoietic and leukemic stem cells. Cell Stem Cell. 2012;11:207–19. https://doi.org/10.1016/j.stem.2012.05.021.CrossRefPubMedPubMedCentral

11.

Qi W, Li Z, Xia L, et al. LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells. Sci Rep. 2019;9:16185. https://doi.org/10.1038/s41598-019-52837-8.ADSCrossRefPubMedPubMedCentral

12.

Mancini A, Xavier-Magalhães A, Woods WS, et al. Disruption of the β1L isoform of GABP reverses glioblastoma replicative immortality in a TERT promoter mutation-dependent manner. Cancer Cell. 2018;34:513-28.e8. https://doi.org/10.1016/j.ccell.2018.08.003.CrossRefPubMedPubMedCentral

13.

Lemasters JJ. Evolution of voltage-dependent anion channel function: from molecular sieve to governator to actuator of ferroptosis. Front Oncol. 2017;7:303. https://doi.org/10.3389/fonc.2017.00303.CrossRefPubMedPubMedCentral

14.

Uhlén M, Björling E, Agaton C, et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics. 2005;4:1920–32. https://doi.org/10.1074/mcp.M500279-MCP200.CrossRefPubMed

15.

Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–60. https://doi.org/10.1093/nar/gkz430.CrossRefPubMedPubMedCentral

16.

Ji Z, Vokes SA, Dang CV, Ji H. Turning publicly available gene expression data into discoveries using gene set context analysis. Nucleic Acids Res. 2016;44: e8. https://doi.org/10.1093/nar/gkv873.CrossRefPubMed

17.

Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. https://doi.org/10.3322/caac.21492.CrossRefPubMed

18.

National Health Commission of PRC. Chinese guidelines for diagnosis and treatment of primary lung cancer 2018 (English version). Chin J Cancer Res. 2019;31:1–28. https://doi.org/10.21147/j.issn.1000-9604.2019.01.01.CrossRef

19.

Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54. https://doi.org/10.1038/nature25183.ADSCrossRefPubMed

20.

Rocco D, Della Gravara L, Battiloro C, Gridelli C. The role of combination chemo-immunotherapy in advanced non-small cell lung cancer. Expert Rev Anticancer Ther. 2019;19:561–8. https://doi.org/10.1080/14737140.2019.1631800.CrossRefPubMed

21.

Seth A, Watson DK. ETS transcription factors and their emerging roles in human cancer. Eur J Cancer. 2005;41:2462–78. https://doi.org/10.1016/j.ejca.2005.08.013.CrossRefPubMed

22.

Wang Y, Wu Y, Li J, Li J, Che G. Clinicopathological and prognostic significance of thyroid transcription factor-1 expression in small cell lung cancer: a systemic review and meta-analysis. Pathol Res Pract. 2019;215: 152706. https://doi.org/10.1016/j.prp.2019.152706.CrossRefPubMed

23.

Rice SJ, Liu X, Hyland V, Liu Z, Belani CP. Mutations in genes connected with the TCF7L2 transcription factor are associated with a poor prognosis in non-small cell lung cancer. Lung Cancer. 2020;141:97–100. https://doi.org/10.1016/j.lungcan.2020.01.015.CrossRefPubMed

24.

Sharrocks AD, Brown AL, Ling Y, Yates PR. The ETS-domain transcription factor family. Int J Biochem Cell Biol. 1997;29:1371–87. https://doi.org/10.1016/s1357-2725(97)00086-1.CrossRefPubMed

25.

Scarpulla RC. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta. 2002;1576:1–14. https://doi.org/10.1016/s0167-4781(02)00343-3.CrossRefPubMed

26.

Genuario RR, Perry RP. The GA-binding protein can serve as both an activator and repressor of ribosomal protein gene transcription. J Biol Chem. 1996;271:4388–95. https://doi.org/10.1074/jbc.271.8.4388.CrossRefPubMed

27.

Hauck L, Kaba RG, Lipp M, Dietz R, von Harsdorf R. Regulation of E2F1-dependent gene transcription and apoptosis by the ETS-related transcription factor GABPgamma1. Mol Cell Biol. 2002;22:2147–58. https://doi.org/10.1128/mcb.22.7.2147-2158.2002.CrossRefPubMedPubMedCentral

28.

Trojanowska M. Ets factors and regulation of the extracellular matrix. Oncogene. 2000;19:6464–71. https://doi.org/10.1038/sj.onc.1204043.CrossRefPubMed

29.

Atlas E, Stramwasser M, Whiskin K, Mueller CR. GA-binding protein alpha/beta is a critical regulator of the BRCA1 promoter. Oncogene. 2000;19:1933–40. https://doi.org/10.1038/sj.onc.1203516.CrossRefPubMed

30.

Sannino F, Sansone C, Galasso C, et al. Pseudoalteromonas haloplanktis TAC125 produces 4-hydroxybenzoic acid that induces pyroptosis in human A459 lung adenocarcinoma cells. Sci Rep. 2018;8:1190. https://doi.org/10.1038/s41598-018-19536-2.ADSCrossRefPubMedPubMedCentral

31.

Kar A, Gutierrez-Hartmann A. Molecular mechanisms of ETS transcription factor-mediated tumorigenesis. Crit Rev Biochem Mol Biol. 2013;48:522–43. https://doi.org/10.3109/10409238.2013.838202.CrossRefPubMedPubMedCentral

32.

Jain S, Pathak K, Vaidya A. Molecular therapy using siRNA: Recent trends and advances of multi target inhibition of cancer growth. Int J Biol Macromol. 2018;116:880–92. https://doi.org/10.1016/j.ijbiomac.2018.05.077.CrossRefPubMed

33.

Chen J, Xie J. Progress on RNAi-based molecular medicines. Int J Nanomedicine. 2012;7:3971–80. https://doi.org/10.2147/ijn.S31897.CrossRefPubMedPubMedCentral

34.

VandenDriessche T, Thorrez L, Naldini L, et al. Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo. Blood. 2002;100:813–22. https://doi.org/10.1182/blood.v100.3.813.CrossRefPubMed

35.

Chen SC, Yen MC, Chen FW, et al. Knockdown of GA-binding protein subunit β1 inhibits cell proliferation via p21 induction in renal cell carcinoma. Int J Oncol. 2018;53:886–94. https://doi.org/10.3892/ijo.2018.4411.CrossRefPubMed

36.

Xie J, Xie G, Chen Q, et al. Identification of a novel lncRNA GABPB1-IT1 that is downregulated and predicts a poor prognosis in non-small cell lung cancer. Oncol Lett. 2019;18:838–45. https://doi.org/10.3892/ol.2019.10357.CrossRefPubMedPubMedCentral

37.

Sizemore GM, Pitarresi JR, Balakrishnan S, Ostrowski MC. The ETS family of oncogenic transcription factors in solid tumours. Nat Rev Cancer. 2017;17:337–51. https://doi.org/10.1038/nrc.2017.20.CrossRefPubMed

38.

Buchwalter G, Hickey MM, Cromer A, et al. PDEF promotes luminal differentiation and acts as a survival factor for ER-positive breast cancer cells. Cancer Cell. 2013;23:753–67. https://doi.org/10.1016/j.ccr.2013.04.026.CrossRefPubMedPubMedCentral

39.

Chatterjee P, Choudhary GS, Alswillah T, et al. The TMPRSS2-ERG gene fusion blocks XRCC4-mediated nonhomologous end-joining repair and radiosensitizes prostate cancer cells to PARP inhibition. Mol Cancer Ther. 2015;14:1896–906. https://doi.org/10.1158/1535-7163.Mct-14-0865.CrossRefPubMedPubMedCentral

40.

Yang H, Schramek D, Adam RC, et al. ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas. Elife. 2015;4: e10870. https://doi.org/10.7554/eLife.10870.CrossRefPubMedPubMedCentral

41.

Kollareddy M, Dimitrova E, Vallabhaneni KC, et al. Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities. Nat Commun. 2015;6:7389. https://doi.org/10.1038/ncomms8389.ADSCrossRefPubMed

42.

Oettgen P. The role of ets factors in tumor angiogenesis. J Oncol. 2010;2010: 767384. https://doi.org/10.1155/2010/767384.CrossRefPubMedPubMedCentral

43.

Gallego-Ortega D, Ledger A, Roden DL, et al. ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells. PLoS Biol. 2015;13: e1002330. https://doi.org/10.1371/journal.pbio.1002330.CrossRefPubMedPubMedCentral

Title: GABPB1 plays a cancer-promoting role in non-small cell lung cancer
Authors: Tuo Wang
Cong Cao
Yu Fan
Jialing Xu
Tao Hua
Jie Ding
Zejie Liu
Beili Wang
Juanwen Lian
Publication date: 01-12-2024
Publisher: Springer US
Keywords: NSCLC
NSCLC
Lung Cancer
Lung Cancer
Lung Cancer
Published in: Discover Oncology / Issue 1/2024
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-024-00914-4

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Abstract

Background

Methods

Results

Conclusions

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