Radiation-induced YAP activation confers glioma radioresistance via promoting FGF2 transcription and DNA damage repair

Abstract

Although radiotherapy is a well-known effective non-surgical treatment for malignant gliomas, the therapeutic efficacy is severely limited due to the radioresistance of tumor cells. Previously, we demonstrated that Yes-associated protein (YAP) promotes glioma malignant progression. However, whether YAP plays a role in radioresistance and its potential value in cancer treatment are still unclear. In this study, we found that high YAP expression is associated with poor prognosis in malignant glioma patients undergoing radiotherapy. Research in immortalized cell lines and primary cells from GBM patients revealed that YAP exhibited a radioresistant effect on gliomas via promoting DNA damage repair. Mechanistically, after radiation, YAP was translocated into the nucleus, where it promoted the expression and secretion of FGF2, leading to MAPK–ERK pathway activation. FGF2 is a novel target gene of YAP. Inhibition of YAP–FGF2–MAPK signaling sensitizes gliomas to radiotherapy and prolongs the survival of intracranial cell-derived and patient-derived xenograft models. These results suggest that YAP–FGF2–MAPK is a key mechanism of radioresistance and is an actionable target for improving radiotherapy efficacy.

Functions of Yes-association protein (YAP) in cancer progression and anticancer therapy resistance

“…Treatment with VP in cancer cells inhibits the expression of YAP target genes, such as CYR61, CTGF, AXL, and BIRC5 [148, 149]. In the present study, we found that VP can enhance the sensitivity of radiotherapy in gliomas by inhibiting the activity of YAP [57].…”

“…Lung cancer Maintain stemness properties [39]; promote the expression of cyclin A and MAPK [40] Breast cancer Upregulate the level of FGFBP1 [41], ITGB2 [41], NEGR1 [42], CYR61 [8,42], CTGF [8,42,43], and RHAMM [44] Gastric cancer Increase c-Fos expression [45]; repress the protein level of p21 [46] and tumor suppressor microRNA [47,48] Hepatocellular carcinoma Promote the expression of target genes [10,49,50]; reduce cellular senescence [51] Colorectal cancer Inhibit PTEN [52]; rescue cell viability [53]; promote the epithelial-mesenchymal transition [53] Pancreatic ductal adenocarcinoma Drive tumor initiation and activate the cell cycle [54] Glioma Enhance Wnt/β-catenin signaling [28], N-cadherin, Twist [55]; promote autophagy mediated by HMGB1 [56]; exhibit a radioresistant effect [57] 4…”

“…Other studies in glioma cells revealed that YAP exhibits a radioresistant function by increasing DNA damage repair. Inhibition of YAP-FGF2-MAPK signaling sensitizes gliomas to radiotherapy and extends the survival of xenograft models [57]. Furthermore, the inhibition of MST1 promotes the proliferation and growth of glioma cells and inhibits apoptosis.…”

“…Activation of the YAP-FGF2-MAPK pathway contributes to the enhancement of DNA repair, promoting cell cycle progression and inhibition of apoptosis, resulting in glioma cell survival following radiation. Blocking YAP-FGF2-MAPK by AZD4547 sensitizes gliomas to radiotherapy [57].…”

Cell survival after DNA damage in the comet assay

“…However, we expect that other cell types might react differently. While some tumor cell lines overexpress certain DNA repair genes (Erasimus et al 2016 ; Zhang et al 2021 ), stem cells are thought to react sensitively with cell death to DNA damage (Weeden and Asselin-Labat 2018 ). Whereas cell lines or primary lymphocytes are used for routine mutagenicity testing, tumors arise from mutations in stem cells and the tumor cells are relevant for identification of sensitivity towards chemotherapeutic DNA-damaging agents.…”