Yes-associated protein 1 (YAP1) is a transcriptional coactivator that is most prominently expressed in normal adult liver and biliary epithelial cells (BECs) during development . It can activate transcription enhancer-associated domain transcription factors after inactivation of the Hippo signaling pathway, thereby regulating biological processes such as proliferation, survival and differentiation. Many cancers rely on the continuous expression of YAP1 to achieve cell proliferation, survival and tumorigenesis.

（Data source: Molina L, et al. Semin Liver Dis. 2022）

YAP1 regulation:

YAP1 is a transcriptional regulator, it does not contain a DNA binding domain. Its transcriptional regulatory function depends on interactions with several other proteins, such as transcription factors (such as TEAD, RUNX2, SMAD) and chromatin remodeling proteins.

（Data source: Szulzewsky F, et al. Dev Biol. 2021）

YAP1 is regulated by:

The first mechanism of YAP1 inactivation is mediated by the exclusion of YAP1 protein from the nucleus. Even under steady-state conditions, YAP1 continuously shuttles between the nucleus and cytoplasm, and the transition between nuclear or cytoplasmic localization is a dynamic process regulated by multiple factors and processes.

（Data source: Manning SA, et al. Development. 2020）

The second mechanism leading to YAP1 inactivation is mediated by proteasomal degradation. Phosphorylation of YAP1 at S397 by LATS1/2 triggers further phosphorylation of YAP1 by CK1δ/ɛ, leading to the formation of a phosphorylated degron, which triggers ubiquitination and subsequent degradation of YAP1 by the SCFβ-TRCP E3 ubiquitin ligase.

（Data source: Zhao B, et al. Genes Dev. 2010）

YAP1 and cancer:

In recent years, elevated YAP1 activity and nuclear staining have been consistently observed in human cancer types and are often associated with poor prognostic outcomes. Dysregulation and constitutive activation of YAP1 have been linked to cancer initiation, progression, invasion, and therapeutic resistance, functions largely attributed to pro-survival and pro-proliferative transcriptional programs initiated through its interaction with TEAD transcription factors.

（Data source: Shibata M, et al. Int J Cancer. 2018）

YAP1 target gene-related long noncoding RNA 00152 (LINC00152), which is highly expressed in colorectal cancer (CRC), can act as a competitive endogenous RNA to regulate FSCN1 expression together with miR-632 and miR-185-3p, thereby promoting tumor malignant proliferation and metastasis.

（Data source: Ou C, et al. Adv Sci (Weinh). 2019）

YAP1 can inhibit hepatocyte ferritin phagocytosis-mediated ferroptosis, and YAP1 deficiency aggravates sepsis-induced liver damage.

(Data source: Wang J, et al. Cell Biosci. 2022)

In human pancreatic cancer cells, YAP1 forms a complex with ZEB1 to activate ITGA3 transcription, which has a significant impact on pancreatic cancer metastasis and epithelial-mesenchymal transition (EMT) plasticity.

(Data source: Liu M, et al. Gastroenterology. 2021)

YAP1 and treatment:

Currently, small molecule inhibitors targeting YAP1 function are mainly designed to activate the tumor-suppressing Hippo kinase pathway, but they are ineffective against tumors with inactivating mutations in Hippo pathway members, tumors with YAP1 overactivation through Hippo-independent pathways, or YAP1 fusion-positive tumors. Therefore, it remains to be seen whether anti-YAP1 therapy is sufficient to inhibit the growth of human tumors that show activated YAP signaling.

Elsewhere, a recent study exploring the involvement of YAP1 in the tendon aging process showed that regeneration of tendon stem/progenitor cells through platelet-derived exosomes loaded with recombinant YAP1 to achieve functional tendon regeneration has broad clinical application prospects.

(Data source: Lu J, et al. Acta Biomater. 2023)

Conclusion

YAP1 activity may not be a true oncogenic driver, but rather a consequence of aberrant oncogenic signaling. In these tumors, YAP1 activity may contribute to aggressiveness and/or resistance to therapy, but inhibition of YAP1 activity alone may not be sufficient to suppress the growth of these tumors. Further studies are needed to determine whether targeting YAP1 in these cancers can be combined with other agents to overcome treatment resistance.