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HOMER3 orchestrates SRC-YAP1 activity that promotes tumor cell growth and antagonizes anti-tumor immunotherapy in prostate cancer

Oncogene volume 44, pages 3895–3908 (2025)Cite this article

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Abstract

(Yes-associated protein 1) YAP1 is frequently activated in human prostate cancers (PCa), but the underlying regulatory mechanism remains elusive. Here, we identified a novel scaffold protein HOMER3 in PCa, that can promote YAP1 activity by disrupting LATS-YAP1 phosphorylation. Mechanistically, HOMER3 overexpression in PCa facilitates the SRC kinase to phosphorylate YAP1 accompanied by counteracting LATS1-mediated YAP1 inhibition, thereby maintaining high YAP1 nuclear localization and transcriptional activity. Accordingly, HOMER3 gain-of-function in PCa cells phenocopies the effect of YAP1 activation, including cell hyperproliferation in vitro and rapid tumor growth in vivo. Additionally, transcriptome analysis revealed that CD274 is consistently upregulated in HOMER3 overexpressing PCa cells and patients, which eventually contributed to an immunosuppressive phenotype. More importantly, blocking SRC kinase-mediated YAP1 activation improved the immunotherapy-insensitive phenotypes in PCa caused by HOMER3 overexpression. Taken together, our findings define a novel kinase-substrate interactive platform for HOMER3 to orchestrate YAP1 activity in PCa. Targeting SRC-YAP1 oncogenic axis provides new insights into the therapeutic potential for PCa patients carried HOMER3 overexpression.

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Fig. 1: The scaffold protein HOMER3 interacts with the YAP1 as well as its major upstream kinase SRC and LATS.
Fig. 2: The scaffold protein HOMER3 alters the interaction of SRC and LATS1 kinase with YAP1 to modulate its activity in PCa.
Fig. 3: The clinical implications of HOMER3 expression in PCa.
Fig. 4: HOMER3 overexpression promotes PCa cell proliferation and xenograft growth.
Fig. 5: The oncogenic HOMER3-YAP1 axis coregulates PD-L1 protein expression and promotes PCa immunosuppression.
Fig. 6: PD-L1 blockade combined with Bosutinib achieves synergistic effects on anti-tumor immunity in PCa.
Fig. 7: HOMER3 orchestrates SRC-YAP1 activity that promotes tumor cell growth and antagonizes anti-tumor immunotherapy in prostate cancer.

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Data availability

The datasets used in the current study are available from the corresponding author on reasonable request.

References

  1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49.

    PubMed  Google Scholar 

  2. Gong J, Kim DM, Freeman MR, Kim H, Ellis L, Smith B, et al. Genetic and biological drivers of prostate cancer disparities in Black men. Nat Rev Urol. 2024;21:274–89.

    Article  CAS  PubMed  Google Scholar 

  3. Corres-Mendizabal J, Zacchi F, Martín-Martín N, Mateo J, Carracedo A. Metastatic hormone-naïve prostate cancer: a distinct biological entity. Trends Cancer. 2024;10:825–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bergengren O, Pekala KR, Matsoukas K, Fainberg J, Mungovan SF, Bratt O, et al. 2022 update on prostate cancer epidemiology and risk factors-a systematic review. Eur Urol. 2023;84:191–206.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nguyen LT, Tretiakova MS, Silvis MR, Lucas J, Klezovitch O, Coleman I, et al. ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell. 2015;27:797–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li Q, Wang M, Hu Y, Zhao E, Li J, Ren L, et al. MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer. Theranostics. 2021;11:5794–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schirmer AU, Driver LM, Zhao MT, Wells CI, Pickett JE, O’Bryne SN, et al. Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther. 2022;30:485–500.

    Article  CAS  PubMed  Google Scholar 

  8. Gu Y, Wu S, Fan J, Meng Z, Gao G, Liu T, et al. CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression. Cell Death Dis. 2024;15:1–12.

    Article  CAS  Google Scholar 

  9. Wang K, Ma F, Arai S, Wang Y, Varkaris A, Poluben L, et al. WNT5a signaling through ROR2 activates the hippo pathway to suppress YAP1 activity and tumor growth. Cancer Res. 2023;83:1016–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bainbridge A, Walker S, Smith J, Patterson K, Dutt A, Ng YM, et al. IKBKE activity enhances AR levels in advanced prostate cancer via modulation of the Hippo pathway. Nucleic Acids Res. 2020;48:5366–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kuser-Abali G, Alptekin A, Lewis M, Garraway IP, Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer. Nat Commun. 2015;6:8126.

    Article  PubMed  Google Scholar 

  12. Zhou P-J, Xue W, Peng J, Wang Y, Wei L, Yang Z, et al. Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway. J Exp Clin Cancer Res. 2017;36:139.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Varzavand A, Hacker W, Ma D, Gibson-Corley K, Hawayek M, Tayh OJ, et al. α3β1 integrin suppresses prostate cancer metastasis via regulation of the hippo pathway. Cancer Res. 2016;76:6577–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Song H, Lu T, Han D, Zhang J, Gan L, Xu C, et al. YAP1 inhibition induces phenotype switching of cancer-associated fibroblasts to tumor suppressive in prostate cancer. Cancer Res. 2024;84:3728–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xiao H, Du X, Tao Z, Jing N, Bao S, Gao W, et al. Taurine inhibits ferroptosis mediated by the crosstalk between tumor cells and tumor-associated macrophages in prostate cancer. Adv Sci. 2023;11:2303894.

    Article  Google Scholar 

  16. Han H, Huang Z, Xu C, Seo G, An J, Yang B, et al. Functional annotation of the Hippo pathway somatic mutations in human cancers. Nat Commun. 2024;15:10106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Luo J, Deng L, Zou H, Guo Y, Tong T, Huang M, et al. New insights into the ambivalent role of YAP/TAZ in human cancers. J Exp Clin Cancer Res. 2023;42:130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tong T, Huang M, Yan B, Lin B, Yu J, Teng Q, et al. Hippo signaling modulation and its biological implications in urological malignancies. Mol Asp Med. 2024;98:101280.

    Article  CAS  Google Scholar 

  19. Zhong Z, Jiao Z, Yu F-X. The Hippo signaling pathway in development and regeneration. Cell Rep. 2024;43:113926.

    Article  CAS  PubMed  Google Scholar 

  20. Zhong Z, Meng Z, Yu F-X. Reconstructing the Hippo signaling network. Sci Bull. 2023;68:2307–10.

    Article  CAS  Google Scholar 

  21. Xiong Y, Zhang X, Zhu J, Zhang Y, Pan Y, Wu Y, et al. Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression. Cell Death Differ. 2023;30:1648–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pulkkinen HH, Kiema M, Lappalainen JP, Toropainen A, Beter M, Tirronen A, et al. BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF. Angiogenesis. 2021;24:129–44.

    Article  CAS  PubMed  Google Scholar 

  23. Gu Y, Wang Y, Sha Z, He C, Zhu Y, Li J, et al. Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers. Cell Rep. 2022;40:111296.

    Article  CAS  PubMed  Google Scholar 

  24. Su D, Li Y, Zhang W, Gao H, Cheng Y, Hou Y et al. SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling. J Clin Invest. 2023;133. https://doi.org/10.1172/JCI168888.

  25. Li F-L, Fu V, Liu G, Tang T, Konradi AW, Peng X, et al. Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides. Nat Chem Biol. 2022;18:1076–86.

    Article  CAS  PubMed  Google Scholar 

  26. Qi S, Zhu Y, Liu X, Li P, Wang Y, Zeng Y, et al. WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy. Mol Cell. 2022;82:1850–1864.e7.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu R, Liu X, Zhang X, Zhong Z, Qi S, Jin R, et al. Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo. Cell Rep. Med. 2024;5:101763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xue S, Chen X, Qiu G, Liao H, Qiang Z, Zhang Z et al. CLK1 Activates YAP to Promote Intrahepatic Cholangiocarcinogenesis. Cancer Res. 2024. https://doi.org/10.1158/0008-5472.CAN-24-0147.

  29. Liu Q, He L, Li S, Li F, Deng G, Huang X, et al. HOMER3 facilitates growth factor-mediated β-Catenin tyrosine phosphorylation and activation to promote metastasis in triple negative breast cancer. J Hematol OncolJ Hematol Oncol. 2021;14:6.

    Article  CAS  Google Scholar 

  30. Chu Y, Dai E, Li Y, Han G, Pei G, Ingram DR, et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat Med. 2023;29:1550–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lu K-H, Tounsi A, Shridhar N, Küblbeck G, Klevenz A, Prokosch S et al. Dickkopf-3 contributes to the regulation of anti-tumor immune responses by mesenchymal stem cells. Front Immunol. 2015;6. https://doi.org/10.3389/fimmu.2015.00645.

  32. Fang X, Bogomolovas J, Trexler C, Chen J. The BAG3-dependent and -independent roles of cardiac small heat shock proteins. JCI Insight. 2019;4. https://doi.org/10.1172/jci.insight.126464.

  33. ElTanbouly MA, Noelle RJ. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat Rev Immunol. 2021;21:257–67.

    Article  CAS  PubMed  Google Scholar 

  34. Yakou MH, Ghilas S, Tran K, Liao Y, Afshar-Sterle S, Kumari A, et al. TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma. Sci Immunol. 2023;8:eadf2163.

    Article  CAS  PubMed  Google Scholar 

  35. Bian X, Wang W, Abudurexiti M, Zhang X, Ma W, Shi G, et al. Integration analysis of single-cell multi-omics reveals prostate cancer heterogeneity. Adv Sci Weinh Baden-Wurtt Ger. 2024;11:e2305724.

    Google Scholar 

  36. Chen S, Zhu G, Yang Y, Wang F, Xiao Y-T, Zhang N, et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat Cell Biol. 2021;23:87–98.

    Article  CAS  PubMed  Google Scholar 

  37. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27:109–18.

    Article  CAS  PubMed  Google Scholar 

  38. Hayashi MK, Tang C, Verpelli C, Narayanan R, Stearns MH, Xu R-M, et al. The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell. 2009;137:159–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shiraishi-Yamaguchi Y, Furuichi T. The Homer family proteins. Genome Biol. 2007;8:206.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Peixoto A, Ferreira D, Azevedo R, Freitas R, Fernandes E, Relvas-Santos M, et al. Glycoproteomics identifies HOMER3 as a potentially targetable biomarker triggered by hypoxia and glucose deprivation in bladder cancer. J Exp Clin Cancer Res. 2021;40:191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sun T, Song C, Zhao G, Feng S, Wei J, Zhang L, et al. HOMER3 promotes non-small cell lung cancer growth and metastasis primarily through GABPB1-mediated mitochondrial metabolism. Cell Death Dis. 2023;14:1–11.

    Article  Google Scholar 

  42. Luo J, Zou H, Guo Y, Tong T, Ye L, Zhu C, et al. SRC kinase-mediated signaling pathways and targeted therapies in breast cancer. Breast Cancer Res. 2022;24:99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Poh AR, Ernst M. Functional roles of SRC signaling in pancreatic cancer: recent insights provide novel therapeutic opportunities. Oncogene. 2023;42:1786–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chessa TAM, Jung P, Anwar A, Suire S, Anderson KE, Barneda D, et al. PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate. Mol Cell. 2023;83:2991–3009.e13.

    Article  CAS  PubMed  Google Scholar 

  45. Teng Y, Cai Y, Pi W, Gao L, Shay C. Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity. J Hematol OncolJ Hematol Oncol. 2017;10:118.

    Article  Google Scholar 

  46. Moro L, Simoneschi D, Kurz E, Arbini AA, Jang S, Guaragnella N, et al. Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis. Nat Cell Biol. 2020;22:1130–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pu T, Wang J, Wei J, Zeng A, Zhang J, Chen J, et al. Stromal-derived MAOB promotes prostate cancer growth and progression. Sci Adv. 2024;10:eadi4935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sridaran D, Chouhan S, Mahajan K, Renganathan A, Weimholt C, Bhagwat S, et al. Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nat Commun. 2022;13:6929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li X-F, Selli C, Zhou H-L, Cao J, Wu S, Ma R-Y, et al. Macrophages promote anti-androgen resistance in prostate cancer bone disease. J Exp Med. 2023;220:e20221007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

mRNA-seq and scRNA-seq analysis was assisted by Guangzhou Genedenovo Biotechnology Co., Ltd. (Guangzhou, China). The Data analysis was performed using the OmicShare tools, a free online platform for data analysis (https://www.omicshare.com/tools).

Funding

The present study was funded by the National Natural Science Foundation of China (Grant No. 82272689 to Jun P and 82072901 to Peng L), Shenzhen Basic Science Research (JCYJ20190809164617205 to Jun P), the Sanming Project of Medicine in Shenzhen (SZSM202011011 to Jun P), the Shenzhen Medical Research Fund (A2302037 to Mengjun H), the Research Start-up Fund of Part-time PI, SAHSYSU (ZSQYJZPI202003 to Jun P), the Shenzhen Science and Technology Innovation Commission (JCYJ20210324120409026 to Peng L), and the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2021A1515111052 to Jun P).

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Author notes

  1. These authors contributed equally: Tongyu Tong, Hanqi Lei.

Authors and Affiliations

  1. Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China

    Tongyu Tong, Hanqi Lei, Mengjun Huang, Qiliang Teng, Fei Cao & Jun Pang

  2. Scientific Research Center, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China

    Tongyu Tong, Hanqi Lei, Mengjun Huang, Hailin Zou, Yibo Guo, Juan Luo & Peng Li

  3. Department of Pathology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China

    Zheng Yang

  4. Yorba Linda High School, Yorba Linda, CA, USA

    Xuyin Dai

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Contributions

Tongyu Tong and Peng Li developed the concept and designed this work. Tongyu Tong, Hanqi Lei, Mengjun Huang, Hailin Zou, Yibo Guo, Qiliang Teng and Fei Cao performed the experiments and carried out the data acquisition. Zheng Yang performed pathological analysis. Peng Li, Jun Pang and Mengjun Huang provided funding acquisition. Tongyu Tong, Hanqi Lei and Juan Luo performed data analysis. Tongyu Tong, Xuyin Dai, Peng Li and Jun Pang edited and revised the manuscript. All authors read and approved this manuscript.

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Correspondence to Jun Pang or Peng Li.

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Written informed consent was obtained from all patients and the study was approved by the Ethics Committee of the Seventh Affiliated Hospital, Sun Yat-sen University (KY-2024-069-02). Animal experiments were performed according to the Health Guide for the Care and Use of Laboratory Animals approved by the Institutional Animal Care and Use Committee of Sun Yat-Sen University (SYSU-IACUC-2024-002513). All methods were performed in accordance with relevant guidelines and regulations.

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Tong, T., Lei, H., Huang, M. et al. HOMER3 orchestrates SRC-YAP1 activity that promotes tumor cell growth and antagonizes anti-tumor immunotherapy in prostate cancer. Oncogene 44, 3895–3908 (2025). https://doi.org/10.1038/s41388-025-03548-0

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