Role of YAP1 in Pancreatic Cancer
Yes-associated protein 1 (YAP1) is a key regulator in the Hippo signaling pathway, a pathway crucial for controlling cell growth, tissue development, and organ size. In cancer, including pancreatic ductal adenocarcinoma (PDAC), YAP1 becomes dysregulated, playing a significant role in tumor progression, metastasis, and immune evasion. It acts as a transcriptional co-activator, promoting the expression of genes that drive cancer cell proliferation, survival, and resistance to therapies.
In PDAC, YAP1 is closely linked to epithelial–mesenchymal transition (EMT), a biological process where cancer cells lose their epithelial characteristics and gain mesenchymal traits, making them more motile and invasive. YAP1 interacts with transcription factors like ZEB1 to enhance EMT, leading to metastatic plasticity, which allows pancreatic cancer cells to spread to other organs more effectively.
YAP1 also contributes to immune suppression in PDAC by promoting the secretion of immunosuppressive cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8). These cytokines cause T-cell exhaustion and recruit regulatory immune cells, helping the tumor evade immune system attacks. Furthermore, YAP1 directly increases PD-L1 expression on tumor cells, enabling them to escape destruction by T-cells.
Recent research has uncovered that YAP1 undergoes glutamylation—a protein modification—regulated by the enzyme GLS2, which enhances its activity. This modification promotes YAP1’s nuclear translocation, driving the expression of survival genes like PD-L1 and worsening immune evasion. Targeting YAP1 and its associated pathways offers great potential for improving PDAC treatment, especially in overcoming resistance to immunotherapy.
