Yes-associated protein

Overview

Yes-associated protein (YAP) is a transcriptional coactivator and the principal downstream effector of the Hippo signaling pathway, a highly conserved kinase cascade that governs organ size, tissue homeostasis, and cellular proliferation. Originally identified as a binding partner of the Src-family kinase Yes, YAP lacks intrinsic DNA-binding activity and instead functions by partnering with transcription factors — most notably the TEAD family — to drive expression of genes promoting cell growth, survival, and stemness. Under conditions of active Hippo signaling, the kinases LATS1 and LATS2 phosphorylate YAP, triggering its cytoplasmic sequestration and proteasomal degradation. When upstream Hippo kinases are lost or suppressed, YAP accumulates in the nucleus and operates as an oncogenic driver across a broad spectrum of human malignancies.

Beyond its canonical role in the Hippo pathway, YAP functions as a mechanotransducer, sensing and relaying physical cues from the extracellular matrix (ECM) through integrin-mediated adhesion complexes and cytoskeletal tension. Its closely related paralog, TAZ (transcriptional coactivator with PDZ-binding motif), frequently acts in concert with YAP, and the two proteins are often studied together in the context of mechanobiology and cancer. YAP hyperactivation has been documented in uveal melanoma, glioblastoma, osteosarcoma, colorectal cancer, and numerous other solid tumors, positioning it as a high-priority therapeutic target in oncology.

Focus of Latest Publications

Recent publications reflect intensifying efforts to target YAP across multiple cancer types, using diverse modalities ranging from nucleic acid therapeutics and nanomedicine to small-molecule inhibitors and hydrogel-based drug delivery.

Uveal melanoma and mRNA-based LATS1 restoration. A 2026 study published in the Journal of Controlled Release addressed YAP's constitutive activation in uveal melanoma (UM), where loss of the upstream Hippo kinase LATS1 prevents YAP phosphorylation and cytoplasmic retention. Investigators designed lipid nanoparticles (LNPs) formulated with the ionizable lipid SM102 to deliver LATS1 messenger RNA via intravitreal administration, restoring kinase function and thereby suppressing oncogenic YAP signaling. This approach was evaluated in an orthotopic UM mouse model as well as liver metastasis and post-surgical recurrence models, demonstrating that re-engaging the LATS1–YAP axis through nucleic acid delivery represents a viable therapeutic strategy for an intraocular tumor with limited treatment options.

Osteosarcoma and cisplatin-induced epigenomic remodeling. A study in Biochemistry (2026) investigated how the chemotherapeutic agent cisplatin — acting through the induction of oxidative stress — engages YAP to modulate the cancer epigenome in osteosarcoma cells. The findings revealed that cisplatin-induced oxidative stress activates YAP, which in turn promotes the accumulation of repressive chromatin marks (including those associated with EZH2 activity), potentially contributing to the survival of residual tumor cells. Critically, pharmacological inhibition or genetic ablation of YAP attenuated the cisplatin-induced accumulation of these repressive epigenetic marks, implicating YAP as a mediator of epigenomic adaptation to chemotherapy and a contributor to treatment resistance. Antioxidants such as N-acetyl cysteine were used as mechanistic probes to confirm the role of oxidative stress upstream of YAP activation.

Photothermal immunotherapy and adenosine-YAP crosstalk. A 2026 paper in ACS Applied Materials & Interfaces described a biodegradable nickel phosphide nanoparticle system engineered to simultaneously modulate adenosine metabolism and inhibit the Hippo–YAP axis for synergistic photothermal immunotherapy. The study reported a dual mechanism: elevated adenosine (Ado) in the tumor microenvironment activates Hippo signaling, which in turn upregulates YAP expression and promotes tumor growth, while phosphate ions released from nanoparticle degradation inhibit autophagy and resveratrol cargo triggers YAP downregulation. By disrupting both arms, the system suppressed cancer cell proliferation while potentiating immune responses — including those mediated by cytotoxic T cells — against the tumor.

Glioblastoma, radioresistance, and PRMT5-dependent YAP methylation. Research published in Cancer Letters (2026) identified a post-translational mechanism by which YAP contributes to glioblastoma (GBM) tumorigenicity and radioresistance. The study demonstrated that PRMT5, a protein arginine methyltransferase, methylates YAP to sustain its hyperactivation, driving the initiation and progression of GBM. Inhibition of PRMT5-dependent YAP methylation attenuated both tumorigenic potential and resistance to radiotherapy, uncovering an epigenetic regulatory layer of YAP activity with potential clinical relevance for a cancer type where checkpoint inhibitor has shown limited efficacy and standard-of-care radiotherapy frequently fails.

Colorectal cancer and mechanotransduction blockade. A study in the Journal of Nanobiotechnology (2026) developed biomimetic nanodecoys designed to remodel the mechano-immune microenvironment in colorectal cancer. These particles were shown to inhibit the Integrin–FAK–YAP mechanotransduction axis, leading to YAP cytoplasmic sequestration and reduced cytoskeletal tension. By dampening YAP-driven mechanical signaling, the nanodecoys potentiated checkpoint blockade immunotherapy, suggesting that mechanosensory YAP activity contributes to immune exclusion in the tumor microenvironment.

Multidrug resistance and ECM biomechanical decoupling. A review article in Molecular Cancer (2026) highlighted YAP and TAZ as central mediators of cancer multidrug resistance through mechanotransduction. The strategy described involves biomechanical softening of the ECM via smart injectable hydrogels to decouple YAP/TAZ-driven mechanosignaling, followed by metabolic disruption of hypoxia-driven bioenergetics, aiming to overcome resistance in solid tumors.

Key Publications

May Cisplatin-Induced Oxidative Stress Regulates YAP to Modulate Epigenome Promoting the Survival of Osteosarcoma Cells. (Biochemistry, 2026, PMID 41980058): "Importantly, pharmacological inhibition or genetic ablation of YAP attenuated the CDDP-induced accumulation of repressive marks."
May Intravitreal delivery of LATS1 mRNA by lipid nanoparticles as an effective strategy for uveal melanoma therapy. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 41786044): "in which the key oncogenic driver Yes-associated protein (YAP) is persistently activated due to loss of upstream Hippo kinases, including Large Tumor Suppressor Kinase 1 (LATS1)."
Apr Biodegradable Nickel Phosphide Mediated Adenosine Metabolism and Hippo Pathway Inhibition for Synergistic Photothermal Immunotherapy. (ACS applied materials & interfaces, 2026, PMID 42003791): "Meanwhile, the proliferation and growth of cancer cells are suppressed through the synergistic effect of PO43--induced autophagy inhibition and resveratrol-triggered YAP downregulation."
Apr Inhibition of PRMT5-dependent YAP methylation attenuates tumorigenicity and radioresistance in glioblastoma. (Cancer letters, 2026, PMID 41663008): "The hyperactivation of the transcriptional coactivator YAP, a downstream effector of the Hippo pathway, has been implicated in the initiation and progression of human cancers including glioblastoma (GBM), but the underlying mechanisms remain elusive."
Apr Biomimetic nanodecoys remodel the mechano-immune microenvironment to potentiate checkpoint blockade in colorectal cancer. (Journal of nanobiotechnology, 2026, PMID 42002768): "MDPAs were shown to inhibit the Integrin-FAK-YAP mechanotransduction axis, leading to YAP cytoplasmic sequestration and attenuated cytoskeletal tension."
Apr Smart hydrogels for overcoming cancer multidrug resistance. (Molecular cancer, 2026, PMID 41963941): "This approach begins with the biomechanical softening of the extracellular matrix to decouple mechanotransduction driven by Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), followed by the metabolic disruption of hypoxia-driven bioenergetics."