YAP as a therapeutic target in esophageal squamous cell carcinoma: insights and strategies

Abstract

Background: Yes-associated protein (YAP) is a core component of the Hippo pathway, which functions as an oncogene in various cancers. However, emerging evidence has shown that YAP can also act as a tumor suppressor. Therefore, understanding the function and molecular mechanism of YAP is crucial for developing YAP-targeted drugs in tumors.

Methods: A comprehensive literature review was conducted. The review mainly includes the post-translational modification, the regulatory mechanisms and function of YAP in esophageal squamous cell carcinoma (ESCC).

Results: YAP undergoes various post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation and others, which critically regulate its protein stability and transcriptional activity in multiple tumors, particularly ESCC. YAP is highly expressed in ESCC tissues, with its aberrant activation closely correlated with poor prognosis in patients. Additionally, YAP is involved in the progression of ESCC, including tumor migration, invasion, proliferation, cell stemness, apoptosis, therapeutic resistance, and immunity. In ESCC, YAP has been confirmed to be regulated by multiple upstream regulators, such as E3 ubiquitin ligases and kinases, thereby influencing the ESCC progression. However, there are still few drugs available clinically for YAP-targeted therapy, which requires further research. In this review, we systematically synthesize the biological roles and regulatory mechanisms of YAP in ESCC and outline potential research directions for YAP-targeted therapies, aiming to provide novel insights for precision medicine in ESCC.

Conclusion: YAP is closely correlated to ESCC progression, and it could be a promising target for ESCC treatment.

Keywords: Esophageal squamous cell carcinoma; YAP; hippo pathway; therapeutic strategy.

Figure 1.

YAP protein domain structure. The TID domain is responsible for binding transcription factors; the WW domain serves as protein-protein interaction; the TA domain mediates transcription activation.

Figure 2.

Core components of the hippo pathway in mammalian cells. When hippo signaling pathway is activated, MST1/2 and SAV1 phosphorylate LATS1/2 and MOB1, thereby promoting YAP/TAZ phosphorylation. Activated YAP/TAZ binds to 14–3–3 and is degraded via the ubiquitin-proteasome pathway in the cytoplasm. When hippo signaling pathway is inactivated, YAP/TAZ translocate to the nucleus, forming a complex with TEADs to activate transcription of target genes.

Figure 3.

Post-translational modifications of YAP. YAP can be regulated by several post-translational modifications including ubiquitination, methylation, acetylation, glycosylation, phosphorylation, SUMOylation, and lactylation.

Figure 4.

The functions of YAP in ESCC. YAP exerts various functions in ESCC, such as migration, invasion, stemness, immune evasion, radiation resistance, chemoresistance, apoptosis, and proliferation.

Figure 5.

Upstream regulatory factors of YAP in ESCC. In ESCC, YAP activity can be inhibited by several factors including RhBMP-2, miRNAs, SOX2, PARK2, RACO-1, SHARPIN. Moreover, YAP can be activated by Gli1, circAMAMTS6, CDK7, RGS16, RNF106, USP36, ezrin, NEK2, CD155 and C12orf59.

Figure 6.

Targeting YAP for ESCC therapy. Dasatinib inhibits YAP activity through src and PDGFG. Nature botanical, Panobinostat, and temsirolimus can directly inhibit YAP activity. Metformnin can activate AMPK, resulting YAP inhibition by activating LATS1/2 and directly regulating YAP. AFCNC promotes YAP degradation by PML. Verteporfin disrupts the interaction between YAP and TEAD, leading to the transcription inhibition of YAP. Statins inhibit YAP through JUK and small G protein. EGFR inhibitor can block phosphorylation of MOB1, thus activating LATS1/2 and inactivating YAP. JQ-1 can inhibit transcription of YAP target genes. Quisinostat downregulates YAP activity through inhibiting akt/mTOR and MAPK/ERK signaling pathways.