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Targeting YAP in Glioblastoma: A Novel Adjunctive Therapy
to Suppress Tumor Progression and Overcome Therapy
Resistance
Wannawat Khotchawan1,2*, Chanchao Lorthongpanich2, Sith Sathornsumetee3, Pakpoom Kheolamai4
,
Surapol Issaragrisil2,5
1 Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University
2 Siriraj Center of Excellence for Stem Cell Research (SiSCR), Faculty of Medicine, Siriraj Hospital,
Mahidol University
3 Siriraj Center of Research Excellence Management, Faculty of Medicine, Siriraj Hospital, Mahidol University
4 Division of Cell Biology, Faculty of Medicine, Thammasat University
5 Division of Hematology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University
*Corresponding Author E-mail: wannawat.kht@student.mahidol.edu
Background: Abstract
Yes-associated protein (YAP) is a key regulator of cell proliferation and survival in the Hippo
pathway, and its dysregulation drives tumor development and progression in various
cancers. However, the precise role of YAP in glioblastoma (GBM), the most aggressive
brain tumor without effective treatment, remains unclear. Therefore, this study aims to
explore YAP’s function in GBM and evaluate its potential as a therapeutic target, which is
effective in other cancers.
Methods: Results: Public datasets and single-cell RNA sequencing (scRNA-seq) data of GBM were analyzed to
compare YAP expression between GBM and other cells in normal brain tissues. Functional
validation was performed using GBM cell lines (U-251 MG, U-87 MG) and patient-derived
cells from Siriraj Hospital, where YAP expression was modulated via shRNA knockdown
(shYAP) or pharmacological inhibition. Spheroid formation and motility assays were
conducted to assess GBM progression, while chemotherapy sensitivity to the standard
GBM drug (Temozolomide; TMZ) was evaluated by measuring cell viability in YAP
inhibition compared to control.
GBM datasets analysis revealed that YAP expression was significantly increased in tumors
compared to normal tissue and correlated with poor survival. scRNA-seq data analysis
confirmed that among Hippo pathway components, YAP was predominantly expressed in
GBM cells rather than in all cell populations. Functional assays demonstrated that genetic
or pharmacological modulation of YAP significantly suppressed GBM progression, as
evidenced by reduced spheroid formation and decreased motility area and rate (migration
and invasion). Furthermore, YAP inhibition enhanced GBM cell sensitivity to TMZ, as shown
by lower cell viability compared to controls.
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