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TEAD4 predicts poor prognosis and transcriptionally targets PLAGL2 in serous ovarian cancer

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Abstract

The oncogenic function of TEA domain transcription factor 4 (TEAD4) has been confirmed in multiple human malignancies, while its potential role and regulatory mechanism in serous ovarian cancer progression are left unknown. By the gene expression analyses from Gene Expression Profiling Interactive Analysis (GEPIA) database, TEAD4 expression is shown to be up-regulated in serous ovarian cancer samples. Here, we confirmed the high expression of TEAD4 in clinical serous ovarian cancer specimens. In the following functional experiments, we found that TEAD4 overexpression promoted serous ovarian cancer malignant phenotypes, including proliferation, migration and invasion in serous ovarian cancer SK-OV-3 and OVCAR-3 cells, while TEAD4 knockout exerted the opposite function. The tumor growth inhibition of TEAD4 depletion was also affirmed by a Xenograft model in mice. In addition, this phenotypic deterioration induced by TEAD4 overexpression was diminished by PLAG1 like zinc finger 2 (PLAGL2) silencing. More importantly, combined with the results of the dual-luciferase assay, the transcriptional regulation of TEAD4 on PLAGL2 promoter was evidenced. Our results showed that the cancer-promoting gene TEAD4 was involved in serous ovarian cancer progression via targeting PLAGL2 at the transcriptional level.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. Kuroki L, Guntupalli SR. Treatment of epithelial ovarian cancer. BMJ. 2020;9(371): m3773.

    Article  Google Scholar 

  2. Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch. 2012;460(3):237–49.

    Article  PubMed  Google Scholar 

  3. Kaldawy A, Segev Y, Lavie O, Auslender R, Sopik V, Narod SA. Low-grade serous ovarian cancer: a review. Gynecol Oncol. 2016;143(2):433–8.

    Article  PubMed  Google Scholar 

  4. Hoppenot C, Eckert MA, Tienda SM, Lengyel E. Who are the long-term survivors of high grade serous ovarian cancer? Gynecol Oncol. 2018;148(1):204–12.

    Article  PubMed  Google Scholar 

  5. Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L. Molecular characterization of epithelial ovarian cancer: implications for diagnosis and treatment. Int J Mol Sci. 2016;17(12):2113.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Shi Y, Zhou C, Lu H, Cui X, Li J, Jiang S, Zhang H, Zhang R. Ceramide synthase 6 predicts poor prognosis and activates the AKT/mTOR/4EBP1 pathway in high-grade serous ovarian cancer. Am J Transl Res. 2020;12(9):5924–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495–505.

    Article  CAS  PubMed  Google Scholar 

  8. Chen CL, Hsu SC, Chung TY, Chu CY, Wang HJ, Hsiao PW, Yeh SD, Ann DK, Yen Y, Kung HJ. Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells. Nat Commun. 2021;12(1):2398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N, Hirahara S, Stephenson RO, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki EM, Nojima H, Rossant J, Nakao K, Niwa H, Sasaki H. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell. 2009;16(3):398–410.

    Article  CAS  PubMed  Google Scholar 

  10. Holden JK, Cunningham CN. Targeting the Hippo pathway and cancer through the TEAD family of transcription factors. Cancers (Basel). 2018;10(3):81.

    Article  PubMed  Google Scholar 

  11. Gibault F, Sturbaut M, Bailly F, Melnyk P, Cotelle P. Targeting transcriptional enhanced associate domains (TEADs). J Med Chem. 2018;61(12):5057–72.

    Article  CAS  PubMed  Google Scholar 

  12. Huh HD, Kim DH, Jeong HS, Park HW. Regulation of TEAD transcription factors in cancer biology. Cells. 2019;8(6):600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhou Y, Huang T, Cheng AS, Yu J, Kang W, To KF. The TEAD family and its oncogenic role in promoting tumorigenesis. Int J Mol Sci. 2016;17(1):138.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pobbati AV, Hong W. Emerging roles of TEAD transcription factors and its coactivators in cancers. Cancer Biol Ther. 2013;14(5):390–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. He L, Yuan L, Sun Y, Wang P, Zhang H, Feng X, Wang Z, Zhang W, Yang C, Zeng YA, Zhao Y, Chen C, Zhang L. Glucocorticoid receptor signaling activates TEAD4 to promote breast cancer progression. Cancer Res. 2019;79(17):4399–411.

    Article  CAS  PubMed  Google Scholar 

  16. Tang JY, Yu CY, Bao YJ, Chen L, Chen J, Yang SL, Chen HY, Hong J, Fang JY. TEAD4 promotes colorectal tumorigenesis via transcriptionally targeting YAP1. Cell Cycle. 2018;17(1):102–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lim B, Park JL, Kim HJ, Park YK, Kim JH, Sohn HA, Noh SM, Song KS, Kim WH, Kim YS, Kim SY. Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer. Carcinogenesis. 2014;35(5):1020–7.

    Article  CAS  PubMed  Google Scholar 

  18. Xia Y, Chang T, Wang Y, Liu Y, Li W, Li M, Fan HY. YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients. PLoS ONE. 2014;9(3): e91770. https://doi.org/10.1371/journal.pone.0091770. (Erratum in: PLoS One. 2016;11(3):e0152712).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu L, Zhao N, Zhou Z, Chen J, Han S, Zhang X, Bao H, Yuan W, Shu X. PLAGL2 promotes the proliferation and migration of gastric cancer cells via USP37-mediated deubiquitination of Snail1. Theranostics. 2021;11(2):700–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu L, Zhou Z, Han S, Chen J, Liu Z, Zhang X, Yuan W, Ji J, Shu X. PLAGL2 promotes epithelial-mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1. Br J Cancer. 2020;122(4):578–89.

    Article  CAS  PubMed  Google Scholar 

  21. Hu W, Zheng S, Guo H, Dai B, Ni J, Shi Y, Bian H, Li L, Shen Y, Wu M, Tian Z, Liu G, Hossain MA, Yang H, Wang D, Zhang Q, Yu J, Birnbaumer L, Feng J, Yu D, Yang Y. PLAGL2-EGFR-HIF-1/2α signaling loop promotes HCC progression and erlotinib insensitivity. Hepatology. 2021;73(2):674–91.

    Article  CAS  PubMed  Google Scholar 

  22. Majem B, Parrilla A, Jiménez C, Suárez-Cabrera L, Barber M, Marín A, Castellví J, Tamayo G, Moreno-Bueno G, Ponce J, Matias-Guiu X, Alameda F, Romero I, Sánchez JL, Pérez-Benavente A, Moran S, Esteller M, Reventós J, Rigau M, Gil-Moreno A, Segura MF, Santamaría A. MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways. Oncogene. 2019;38(32):6035–50.

    Article  CAS  PubMed  Google Scholar 

  23. Sekiya R, Maeda M, Yuan H, Asano E, Hyodo T, Hasegawa H, Ito S, Shibata K, Hamaguchi M, Kikkawa F, Kajiyama H, Senga T. PLAGL2 regulates actin cytoskeletal architecture and cell migration. Carcinogenesis. 2014;35(9):1993–2001.

    Article  CAS  PubMed  Google Scholar 

  24. Quinn HM, Vogel R, Popp O, Mertins P, Lan L, Messerschmidt C, Landshammer A, Lisek K, Château-Joubert S, Marangoni E, Koren E, Fuchs Y, Birchmeier W. YAP and β-catenin cooperate to drive oncogenesis in basal breast cancer. Cancer Res. 2021;81(8):2116–27.

    Article  CAS  PubMed  Google Scholar 

  25. Stein C, Bardet AF, Roma G, Bergling S, Clay I, Ruchti A, Agarinis C, Schmelzle T, Bouwmeester T, Schübeler D, Bauer A. YAP1 exerts its transcriptional control via TEAD-mediated activation of enhancers. PLoS Genet. 2015;11(8): e1005465.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Yu T, Song J, Zhou H, Wu T, Liang Z, Du P, Liu CY, Wang G, Cui L, Liu Y. Nuclear TEAD4 with SIX1 overexpression is an independent prognostic marker in the stage I-III colorectal cancer. Cancer Manag Res. 2021;17(13):1581–9.

    Article  CAS  Google Scholar 

  27. Hu Y, Mu H, Deng Z. The transcription factor TEAD4 enhances lung adenocarcinoma progression through enhancing PKM2 mediated glycolysis. Cell Biol Int. 2021;45(10):2063–73.

    Article  CAS  PubMed  Google Scholar 

  28. Wu Y, Li M, Lin J, Hu C. Hippo/TEAD4 signaling pathway as a potential target for the treatment of breast cancer. Oncol Lett. 2021;21(4):313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang Z, Yan Y, Tang P, Cai J, Cao X, Wang Z, Zhang F, Shen B. TEAD4 as a prognostic marker promotes cell migration and invasion of urinary bladder cancer via EMT. Onco Targets Ther. 2021;10(14):937–49.

    Article  Google Scholar 

  30. He S, Gao K, Mao L, Bhushan S, Xiao Z. Gene silencing of transcription factor TEAD4 inhibits esophageal cancer cells by regulating TCF7. Cancer Biother Radiopharm. 2023;38(2):132–9. https://doi.org/10.1089/cbr.2020.3870.

  31. Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer. Cell. 2017;168(4):629–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang WH, Huang Z, Wu J, Ding CC, Murphy SK, Chi JT. A TAZ-ANGPTL4-NOX2 axis regulates ferroptotic cell death and chemoresistance in epithelial ovarian cancer. Mol Cancer Res. 2020;18(1):79–90.

    Article  CAS  PubMed  Google Scholar 

  33. Declercq J, Hensen K, Van De Ven WJ, Chavez M. PLAG proteins: how they influence apoptosis and cell proliferation. Ann N Y Acad Sci. 2003;1010:264–5.

    Article  PubMed  Google Scholar 

  34. Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV, Paik JH, Zhang H, Xiao Y, Perry SR, Hu J, Vinjamoori A, Gan B, Sahin E, Chheda MG, Brennan C, Wang YA, Hahn WC, Chin L, DePinho RA. PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell. 2010;17(5):497–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu B, Lu C, Song YX, Gao P, Sun JX, Chen XW, Wang MX, Dong YL, Xu HM, Wang ZN. The role of pleomorphic adenoma gene-like 2 in gastrointestinal cancer development, progression, and prognosis. Int J Clin Exp Pathol. 2014;7(6):3089–100.

    PubMed  PubMed Central  Google Scholar 

  36. Li N, Li D, Du Y, Su C, Yang C, Lin C, Li X, Hu G. Overexpressed PLAGL2 transcriptionally activates Wnt6 and promotes cancer development in colorectal cancer. Oncol Rep. 2019;41(2):875–84.

    CAS  PubMed  Google Scholar 

  37. Li C, Dong B, Xu X, Li Y, Wang Y, Li X. LncRNA ARAP1-AS1 aggravates the malignant phenotypes of ovarian cancer cells through sponging miR-4735–3p to enhance PLAGL2 expression. Cytotechnology. 2021;73(3):363–72. https://doi.org/10.1007/s10616-021-00463-6. (Erratum in: Cytotechnology. 2022 Feb;74(1):201).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lu LL, Chen XH, Zhang G, Liu ZC, Wu N, Wang H, Qi YF, Wang HS, Cai SH, Du J. CCL21 facilitates chemoresistance and cancer stem cell-like properties of colorectal cancer cells through AKT/GSK-3β/Snail signals. Oxid Med Cell Longev. 2016;2016:5874127.

    Article  PubMed  Google Scholar 

  39. Liu HY, Zhang YY, Zhu BL, Feng FZ, Zhang HT, Yan H, Zhou B. MiR-203a-3p regulates the biological behaviors of ovarian cancer cells through mediating the Akt/GSK-3β/Snail signaling pathway by targeting ATM. J Ovarian Res. 2019;12(1):60.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by Shenyang Young and Middle-aged Innovation Support Project (no. RC190500) and the Natural Science Foundation of Liaoning Province (no. 2020-MS-063).

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  1. Xin Tong and Yi-Si Liu contributed equally to this work and are the co-first authors.

Authors and Affiliations

  1. Department of Interventional, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China

    Xin Tong

  2. Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, China

    Yi-Si Liu, Rui Tong, Wei-Wei Tang, Xue-Mei Li, Chun-Yan Wang & Yong-Peng Wang

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  1. Xin Tong
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Tong, X., Liu, YS., Tong, R. et al. TEAD4 predicts poor prognosis and transcriptionally targets PLAGL2 in serous ovarian cancer. Human Cell 36, 1535–1547 (2023). https://doi.org/10.1007/s13577-023-00908-4

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