The role of YAP1 in survival prediction, immune modulation, and drug response: A pan-cancer perspective

Abstract

IntroductionDysregulation of the Hippo signaling pathway has been implicated in multiple pathologies, including cancer, and YAP1 is the major effector of the pathway. In this study, we assessed the role of YAP1 in prognostic value, immunomodulation, and drug response from a pan-cancer perspective.MethodsWe compared YAP1 expression between normal and cancerous tissues and among different pathologic stages survival analysis and gene set enrichment analysis were performed. Additionally, we performed correlation analyses of YAP1 expression with RNA modification-related gene expression, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint regulator expression, and infiltration of immune cells. Correlations between YAP1 expression and IC50s (half-maximal inhibitory concentrations) of drugs in the CellMiner database were calculated.ResultsWe found that YAP1 was aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications, particularly m6A methylation. High expression of YAP1 was associated with poor survival outcomes in ACC, BLCA, LGG, LUAD, and PAAD. YAP1 expression was negatively correlated with the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, and positively correlated with the infiltration of myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in pan-cancer. Higher YAP1 expression showed upregulation of TGF-β signaling, Hedgehog signaling, and KRAS signaling. IC50s of FDA-approved chemotherapeutic drugs capable of inhibiting DNA synthesis, including teniposide, dacarbazine, and doxorubicin, as well as inhibitors of hypoxia-inducible factor, MCL-1, ribonucleotide reductase, and FASN in clinical trials were negatively correlated with YAP1 expression.DiscussionIn conclusion, YAP1 is aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications. High expression of YAP1 is associated with poor survival outcomes in certain cancer types. YAP1 may promote tumor progression through immunosuppression, particularly by suppressing the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, as well as recruiting MDSCs and CAFs in pan-cancer. The tumor-promoting activity of YAP1 is attributed to the activation of TGF-β, Hedgehog, and KRAS signaling pathways. AZD2858 and varlitinib might be effective in cancer patients with high YAP1 expression.

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy

“…Activated YAP1 upregulates the secretion of IL-6 and TNF-α from tumor cells, as well as colony-stimulating factor 1-3 (CSF1-3), CXC motif chemokine ligand 5(CXCL5), PGE2, COX2, and other factors that recruit MDSCs ( 84 ). Verteporfin, the inhibitor of YAP1, downregulated IL-6, CSF1-3, and CXCL5, which compel MDSCs in tumor ( 85 ). Therefore, YAP1-TEAD complex creates an immunosuppressive microenvironment by stimulating tumor cells to secrete factors that recruit MDSCs, Tregs, and CAFs, which is conducive to the spread and invasion in tumor niche.…”

Four types of adenine-related RNA modification writers -mediated molecular subtypes contribute to predicting clinical outcomes and treatment options in bladder cancer

“…For example, Xueqing Hu et al. have demonstrated that YAP1 may promote BLCA progression through suppressing the CD4+ Th1 cells, T follicular helper cells, NKT cells, infiltration of CD8+ T lymphocytes and activated NK cells ( 22 ). Yuzhen Gao et al.…”

“…Previous studies have reported that TME has close correlation with adenine-related RNA modifications. For example, Xueqing Hu et al have demonstrated that YAP1 may promote BLCA progression through suppressing the CD4+ Th1 cells, T follicular helper cells, NKT cells, infiltration of CD8+ T lymphocytes and activated NK cells (22). Yuzhen Gao et al have reported that m1A regulators mediated three distinct immunophenotype (desert, excluded and inflamed) of in TME -infiltrating immune cells in colon cancer (23).…”

YAP1 promotes the stemness of airway epithelial basal cells and spontaneous formation of lung squamous cell carcinoma in a YAP1KITrp53KO mouse model

“…In the context of NSCLC, studies have shown that YAP1 can promote tumor invasion, immigration and metastasis [14][15][16], and contributes to the stemness maintenance of lung cancer stem cells [17]. The level of nuclear YAP1 is correlated with the poor prognosis of NSCLC [18,19,20], and contributes to the hallmarks of NSCLC [21]. However, current research lacks direct evidence that YAP1 could promote the onset of LSCC.…”