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Loss-of-function mutations of SOX17 lead to YAP/TEAD activation-dependent malignant transformation in endometrial cancer

Oncogene volume 42, pages 322–334 (2023)Cite this article

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Abstract

Aberrant hyperactivation of the Hippo pathway effector YAP/TEAD complex causes tissue overgrowth and tumorigenesis in various cancers, including endometrial cancer (EC). The transcription factor SOX17 (SRY [sex-determining region Y]-box 17) is frequently mutated in EC; however, SOX17 mutations are rare in other cancer types. The molecular mechanisms underlying SOX17 mutation–induced EC tumorigenesis remain poorly understood. Here, we demonstrate that SOX17 serves as a tumor suppressor to restrict the proliferation, migration, invasion, and anchorage-independent growth of EC cells, partly by suppressing the transcriptional outputs of the Hippo-YAP/TEAD pathway. SOX17 binds to TEAD transcription factors through its HMG domain and attenuates the DNA-binding ability of TEAD. SOX17 loss by inactivating mutations leads to the malignant transformation of EC cells, which can be reversed by small-molecule inhibitors of YAP/TEAD or cabozantinib, an FDA-approved drug targeting the YAP/TEAD transcriptional target AXL. Our findings reveal novel molecular mechanisms underlying Hippo-YAP/TEAD pathway–driven EC tumorigenesis, and suggest potential therapeutic strategies targeting the Hippo-YAP/TEAD pathway in SOX17-mutated EC.

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Fig. 1: SOX17 suppresses malignant phenotypes in EC cells.
Fig. 2: SOX17 KO induces molecular and morphologic changes indicative of EMT in Ishikawa cells.
Fig. 3: SOX17 modulates Hippo pathway in EC cells.
Fig. 4: SOX17 directly binds TEADs and attenuates the DNA-binding ability of TEAD1 to inhibit the transcription outputs of Hippo pathway.
Fig. 5: AXL Inhibition partially reverses SOX17 KO–induced malignant phenotypes in EC cells.
Fig. 6: AXL is inversely correlated with SOX17 expression in EC specimens.
Fig. 7: The EC-associated hotspot SOX17 mutants showed attenuated tumor suppressive function without affecting Hippo-YAP pathway activity.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  Google Scholar 

  2. Cancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.

    Article  Google Scholar 

  3. Le Gallo M, O’Hara AJ, Rudd ML, Urick ME, Hansen NF, O’Neil NJ, et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet. 2012;44:1310–5.

    Article  Google Scholar 

  4. Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet. 2016;387:1094–108.

    Article  Google Scholar 

  5. Lilly AJ, Lacaud G, Kouskoff V. SOXF transcription factors in cardiovascular development. Semin Cell Dev Biol. 2017;63:50–57.

    Article  CAS  Google Scholar 

  6. Kim I, Saunders TL, Morrison SJ. SOX17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell. 2007;130:470–83.

    Article  CAS  Google Scholar 

  7. Kanai-Azuma M, Kanai Y, Gad JM, Tajima Y, Taya C, Kurohmaru M, et al. Depletion of definitive gut endoderm in SOX17-null mutant mice. Development. 2002;129:2367–79.

    Article  CAS  Google Scholar 

  8. Kobayashi T, Zhang H, Tang WWC, Irie N, Withey S, Klisch D, et al. Principles of early human development and germ cell program from conserved model systems. Nature. 2017;546:416–20.

    Article  CAS  Google Scholar 

  9. Sakamoto Y, Hara K, Kanai-Azuma M, Matsui T, Miura Y, Tsunekawa N, et al. Redundant roles of SOX17 and SOX18 in early cardiovascular development of mouse embryos. Biochem Biophys Res Commun. 2007;360:539–44.

    Article  CAS  Google Scholar 

  10. Kinnear S, Salamonsen LA, Francois M, Harley V, Evans J. Uterine SOX17: a key player in human endometrial receptivity and embryo implantation. Sci Rep. 2019;9:15495.

    Article  Google Scholar 

  11. Wang X, Li X, Wang T, Wu SP, Jeong JW, Kim TH, et al. SOX17 regulates uterine epithelial-stromal cross-talk acting via a distal enhancer upstream of Ihh. Nat Commun. 2018;9:4421.

    Article  Google Scholar 

  12. Walker CJ, O’Hern MJ, Serna VA, Kurita T, Miranda MA, Sapp CE, et al. Novel SOX17 frameshift mutations in endometrial cancer are functionally distinct from recurrent missense mutations. Oncotarget. 2017;8:68758–68.

    Article  Google Scholar 

  13. Ma S, Meng Z, Chen R, Guan KL. The Hippo Pathway: Biology and Pathophysiology. Annu Rev Biochem. 2019;88:577–604.

    Article  CAS  Google Scholar 

  14. Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24:862–74.

    Article  CAS  Google Scholar 

  15. Stanger BZ. Quit your YAPing: a new target for cancer therapy. Genes Dev. 2012;26:1263–7.

    Article  CAS  Google Scholar 

  16. Mittal V. Epithelial Mesenchymal Transition in Tumor Metastasis. Annu Rev Pathol. 2018;13:395–412.

    Article  CAS  Google Scholar 

  17. Diepenbruck M, Waldmeier L, Ivanek R, Berninger P, Arnold P, van Nimwegen E, et al. Tead2 expression levels control the subcellular distribution of Yap and Taz, zyxin expression and epithelial-mesenchymal transition. J Cell Sci. 2014;127:1523–36.

    CAS  Google Scholar 

  18. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26:1300–5.

    Article  CAS  Google Scholar 

  19. Lin KC, Park HW, Guan KL. Regulation of the Hippo Pathway Transcription Factor TEAD. Trends Biochem Sci. 2017;42:862–72.

    Article  CAS  Google Scholar 

  20. Zhu C, Wei Y, Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019;18:153.

    Article  Google Scholar 

  21. Xu MZ, Chan SW, Liu AM, Wong KF, Fan ST, Chen J, et al. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma. Oncogene. 2010;30:1229–40.

    Article  Google Scholar 

  22. Markowitz JN, Fancher KM. Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. Pharmacotherapy. 2018;38:357–69.

    Article  CAS  Google Scholar 

  23. Azad T, Nouri K, Janse van Rensburg HJ, Maritan SM, Wu L, Hao Y, et al. A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis. Oncogene. 2020;39:334–55.

    Article  CAS  Google Scholar 

  24. Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW, Varmus HE. Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Mol Cell. 1999;4:487–98.

    Article  CAS  Google Scholar 

  25. Merino-Azpitarte M, Lozano E, Perugorria M, Esparza-Baquer A, Erice O, Santos-Laso Á, et al. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J Hepatol. 2017;67:72–83.

    Article  CAS  Google Scholar 

  26. Mukherjee S, Chaturvedi P, Rankin S, Fish M, Wlizla M, Paraiso K, et al. Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network. Elife. 2020;9:e58029.

    Article  CAS  Google Scholar 

  27. Li L, Yang W, Zheng P, Liu XF. SOX17 restrains proliferation and tumor formation by down-regulating activity of the Wnt/β-catenin signaling pathway via trans-suppressing β-catenin in cervical cancer. Cell Death Dis. 2018;9:741.

    Article  CAS  Google Scholar 

  28. Zhu N, Welch C, Wang J, Allen P, Gonzaga-Jauregui C, Ma L, et al. Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease. Genome Med. 2018;10:56.

    Article  Google Scholar 

  29. Ying L, Mills J, French D, Gadue P. OCT4 Coordinates with WNT Signaling to Pre-pattern Chromatin at the SOX17 Locus during Human ES Cell Differentiation into Definitive Endoderm. Stem Cell Rep. 2015;5:490–8.

    Article  CAS  Google Scholar 

  30. Zhang W, Gao Y, Li P, Shi Z, Guo T, Li F, et al. VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res. 2014;24:331–43.

    Article  CAS  Google Scholar 

  31. Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell. 2014;25:166–80.

    Article  CAS  Google Scholar 

  32. Qiao Y, Lin SJ, Chen Y, Voon DC, Zhu F, Chuang LS, et al. RUNX3 is a novel negative regulator of oncogenic TEAD-YAP complex in gastric cancer. Oncogene. 2016;35:2664–74.

    Article  CAS  Google Scholar 

  33. Wissmüller S, Kosian T, Wolf M, Finzsch M, Wegner M. The high-mobility-group domain of Sox proteins interacts with DNA-binding domains of many transcription factors. Nucl Acids Res. 2006;34:1735–44.

    Article  Google Scholar 

  34. Zhang Y, Bao W, Wang K, Lu W, Wang H, Tong H, et al. SOX17 is a tumor suppressor in endometrial cancer. Oncotarget. 2016;7:76036–46.

    Article  Google Scholar 

  35. Dhani NC, Hirte HW, Wang L, Burnier JV, Jain A, Butler MO, et al. Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago, and California Consortia (NCI9322/PHL86). Clin Cancer Res. 2020;26:2477–86.

    Article  CAS  Google Scholar 

  36. Wen X, Wan J, He Q, Wang M, Li S, Jiang M, et al. p190A inactivating mutations cause aberrant RhoA activation and promote malignant transformation via the Hippo-YAP pathway in endometrial cancer. Signal Transduct Target Ther. 2020;5:81.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 91954106 and 81872109 to K.G., No. 81972438 and 82172975 to X.W.), Natural Science Foundation of Shanghai ((No. 18ZR1430100 to K.G.), Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center (SHDC12020107 to X.W.), and Shanghai Sailing Program (No. 22YF1434700 to Y.S.).

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Author notes

  1. These authors contributed equally: Mengfei Wang, Qin Yan, Yunfeng Song.

Authors and Affiliations

  1. Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204, China

    Mengfei Wang, Qin Yan, Yunfeng Song & Xiaoping Wan

  2. Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China

    Zhenbo Zhang

  3. Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China

    Xiaojun Chen

  4. Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204, China

    Kun Gao

  5. Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, China

    Xiaoping Wan

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Contributions

XW and KG conceived of the study. MW acquired the patient samples. MW, QY, and YS performed the experiments and analyzed the data. KG, XW, ZZ, and XC analyzed and interpreted the data. XW and KG wrote and revised the manuscript.

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Correspondence to Kun Gao or Xiaoping Wan.

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The study protocol was approved by the School of Medicine Ethics Committee of Tongji University. Informed consent was obtained from all participants included in this study according to committee regulations.

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Wang, M., Yan, Q., Song, Y. et al. Loss-of-function mutations of SOX17 lead to YAP/TEAD activation-dependent malignant transformation in endometrial cancer. Oncogene 42, 322–334 (2023). https://doi.org/10.1038/s41388-022-02550-0

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