Tumor-Promoting Effects of YAP1 and YAP S127A Overexpression in Prostate Cancer Cells

Yıl 2025, Cilt: 37 Sayı: 4, 354 - 360, 23.12.2025

Filiz Kısaayak Çollak , Ümmühan Demir , Fatma Sağır

https://doi.org/10.7240/jeps.1743240

Öz

Understanding the molecular pathogenesis in cancer is crucial to shed light on novel anti-cancer treatments. YAP1 is important player in Hippo pathway to mediate tissue homeostasis. Aberrant activation of YAP1 has a role in cancer progression. This study aimed to understand the effect of overexpression of YAP1 and non-phosphorylated YAP S127A in prostate cancer progression. After transient overexpression of YAP1 and YAP S127A, the functional assays such as viability, 2D colony formation and soft agar colony formation were applied in LNCaP and PC3 cell lines. Additionally, subcellular localization of overexpressed YAP1 and YAP S127A was investigated. The cell viability was enhanced both in LNCaP and PC3 prostate cancer cell lines upon YAP S127A overexpression, with an increase of 33% in LNCaP and 25% in PC3 cells compared to control . 2D colony formation ability of PC3 cells were elevated in YAP S127A expressing cells compared to both YAP1 expressing cells (p = .037) and controls (p=.0003). The overexpressed YAP1 and YAP S127A were mainly localized to the cytoplasm. Although, the nuclear localization of overexpressed YAP1 and YAP S127A was limited, increased expression of them enhanced tumor promoting functions such as viability and 2D colony formation ability. Notably, these predominantly cytoplasmic YAP1 and YAP S127A despite the S127A mutation's design to resist phosphorylation and promote nuclear accumulation, suggest the presence of alternative regulatory mechanisms. Our results show that YAP1 may play a role in prostate cancer progression. Additional in vitro studies with more prostate cancer models and in vivo experiments are required to understand the biological impact of its cytoplasmic localization.

Anahtar Kelimeler

prostatic neoplasms , cell proliferation , hippo signaling pathway , YAP1

Etik Beyan

This study does not involve the collection of biological samples from human participants, nor does it include any animal experiments. The experiments are conducted solely on cell lines. Therefore, ethics committee approval is not required.

Destekleyen Kurum

The Scientific and Technological Research Council of Turkey (TUBITAK), Istanbul Medeniyet University Scientific Research Grants

Proje Numarası

This work is financially supported by the The Scientific and Technological Research Council of Turkey (TUBITAK) (P. No:114S419) and Istanbul Medeniyet University Scientific Research Grants (FBA-2014-293).

Teşekkür

This work is financially supported by the The Scientific and Technological Research Council of Turkey (TUBITAK) (P. No:114S419) and Istanbul Medeniyet University Scientific Research Grants (FBA-2014-293).

Prostat Kanseri Hücrelerinde YAP1 ve YAP S127A Aşırı Ekspresyonunun Tümör Artırıcı Etkileri

Öz

Kanserin moleküler patogenezini anlamak, yeni anti-kanser tedavilerine ışık tutmak açısından kritik öneme sahiptir. YAP1, Hippo sinyal yolağında doku homeostazını düzenleyen önemli bir bileşendir. YAP1'in anormal aktivasyonu, kanser ilerlemesinde rol oynar. Bu çalışma, YAP1’in ve fosforile olmayan YAP S127A'nın aşırı ifadesinin prostat kanserinin gelişimindeki etkisini anlamayı amaçlamaktadır. YAP1 ve YAP S127A'nın ekzojen ifadesinin ardından, LNCaP ve PC3 hücre hatlarında canlılık, 2D koloni oluşumu ve yumuşak agar koloni oluşumu gibi fonksiyonel analizler uygulandı. Ek olarak, YAP1'in aşırı ifade sonrası hücre içi lokalizasyonu incelendi. YAP S127A aşırı eksprese edildiğinde hücre canlılığı, LNCaP ve PC3 prostat kanseri hücre hatlarında kontrole kıyasla sırasıyla %33 ve %25 oranında artış göstermiştir. PC3 hücrelerinin 2D koloni oluşturma yeteneği; YAP S127A ifade eden hücrelerde, hem YAP1’i ifade eden hücrelere (p=.037) hem de kontrol grubuna (p=.0003) kıyasla daha yüksektir. Aşırı ifade edilen YAP1 ve YAP S127A çoğunlukla sitoplazmada lokalize olmuştur. Bununla birlikte, aşırı ifade edilen YAP1 ve YAP S127A'nın nükleer lokalizasyonu sınırlı olsa da, bu proteinlerin artan ifadesi, hücre canlılığı ve 2D koloni oluşturma yeteneği gibi tümörü destekleyici fonksiyonları güçlendirmiştir. Hem YAP1 hem de YAP S127A, S127A mutasyonunun fosforilasyona dirençli olması ve nükleer birikimi artırması için tasarlanmasına rağmen ağırlıklı olarak sitoplazmada lokalize olmuş olup, bu durum alternatif düzenleyici mekanizmaların varlığını düşündürmektedir. Sonuçlarımız YAP1'in prostat kanseri ilerlemesindeki rolünün önemli göstergeleridir. YAP1'in sitoplazmadaki rolünü anlamak için daha fazla çalışma gereklidir.

Anahtar Kelimeler

prostat kanseri , hücre proliferasyonu , hippo sinyal yolağı , YAP1

Proje Numarası

This work is financially supported by the The Scientific and Technological Research Council of Turkey (TUBITAK) (P. No:114S419) and Istanbul Medeniyet University Scientific Research Grants (FBA-2014-293).

Kaynakça

• Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74:229–263
• Guzman J, Hart M, Weigelt K, et al (2025) The MicroRNA miR-454 and the mediator complex component MED12 are regulators of the androgen receptor pathway in prostate cancer. Scientific Reports 2025 15:1 15:1–11
• Gu Y, Wu S, Fan J, Meng Z, Gao G, Liu T, Wang Q, Xia H, Wang X, Wu K (2024) CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression. Cell Death & Disease 2024 15:1 15:1–12
• Li FL, Guan KL (2022) The two sides of Hippo pathway in cancer. Semin Cancer Biol 85:33–42
• Boopathy GTK, Hong W (2019) Role of Hippo Pathway-YAP/TAZ signaling in angiogenesis. Front Cell Dev Biol 7:440860
• Mokhtari RB, Ashayeri N, Baghaie L, Sambi M, Satari K, Baluch N, Bosykh DA, Szewczuk MR, Chakraborty S (2023) The Hippo Pathway Effectors YAP/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment. Cancers (Basel). 15, 3468.
• Kuser-Abali G, Alptekin A, Lewis M, Garraway IP, Cinar B (2015) YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer. Nature Communications 2015 6:1 6:1–13
• Lee HC, Ou CH, Huang YC, Hou PC, Creighton CJ, Lin YS, Hu CY, Lin SC (2021) YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer. Oncogene 2021 40:13 40:2407–2421
• Zheng G, Yan Z, Zou J, Zou X, Chai K, Zhang G (2025) AR and YAP crosstalk: impacts on therapeutic strategies in prostate cancer. Front Oncol 15:1520808
• Zhou PJ, Wang X, An N, Wei L, Zhang L, Huang X, Zhu HH, Fang YX, Gao WQ (2018) Loss of Par3 promotes prostatic tumorigenesis by enhancing cell growth and changing cell division modes. Oncogene 2018 38:12 38:2192–2205
• Shi Y, Cao T, Sun Y, Xia J, Wang P, Ma J (2019) Nitidine Chloride inhibits cell proliferation and invasion via downregulation of YAP expression in prostate cancer cells. Am J Transl Res 11:709
• Zhang L, Yang S, Chen X, et al (2015) The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells. Mol Cell Biol 35:1350–1362
• Wang R, Du Y, Shang J, Dang X, Niu G (2020) PTPN14 acts as a candidate tumor suppressor in prostate cancer and inhibits cell proliferation and invasion through modulating LATS1/YAP signaling. Mol Cell Probes 53:101642
• Huang SH, Kao YH, Muller CJF, Joubert E, Chuu CP (2020) Aspalathin-rich green Aspalathus linearis extract suppresses migration and invasion of human castration-resistant prostate cancer cells via inhibition of YAP signaling. Phytomedicine 69:153210
• Li X, Lin Y-Y, Tan J-Y, Liu K-L, Shen X-L, Hu Y-J, Yang R-Y (2021) Lappaol F, an anticancer agent, inhibits YAP via transcriptional and post-translational regulation. Pharm Biol 59:617–626
• Kwon H, Kim J, Jho E hoon (2022) Role of the Hippo pathway and mechanisms for controlling cellular localization of YAP/TAZ. FEBS J 289:5798–5818
• Sakabe M, Fan J, Odaka Y, et al (2017) YAP/TAZ-CDC42 signaling regulates vascular tip cell migration. Proc Natl Acad Sci U S A 114:10918–10923
• Wang Y, Wu N, Li J, Zhou D, Liang J, Cao Q, Guan Z, Xu Y, Jiang N (2024) YAP1 Regulates the YAP1/AR/PSA Axis through Autophagy in Castration-Resistant Prostate Cancer and Mediates T-Cell Immune and Inflammatory Cytokine Infiltration. Biomedicines.12(3), 661
• Li X, Zhuo S, Cho YS, Liu Y, Yang Y, Zhu J, Jiang J (2023) YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth. EMBO J. 42: e112184
• Cinar B, Al-Mathkour MM, Khan SA, Moreno CS (2020) Androgen attenuates the inactivating phospho–Ser-127 modification of yes-associated protein 1 (YAP1) and promotes YAP1 nuclear abundance and activity. J Biol Chem 295:8550
• Zheng G, Yan Z, Zou J, Zou X, Chai K, Zhang G (2025) AR and YAP crosstalk: impacts on therapeutic strategies in prostate cancer. Front Oncol.15,1520808