Search Results (89)

Background and Objectives: The Hippo pathway, via Yes-associated protein 1 (YAP1), regulates cell proliferation, apoptosis, and tissue regeneration. Aberrant YAP1 activation is linked to tumor progression and immune evasion in various cancers, including breast carcinoma, despite conflicting evidence on its prognostic value. Preclinical studies have explored drugs targeting YAP1–TEAD interactions, but therapeutic application is limited. Materials and Methods: This study included 50 patients with locally advanced breast cancer, who were assessed by a multidisciplinary tumor board and underwent neoadjuvant treatment per tumor subtype and clinical guidelines. Eligibility required both pre-treatment core biopsy and post-treatment surgical resection samples. Due to the absence of residual tumor in some patients achieving complete pathological response, post-treatment tissue was available and analyzable in 30 patients. YAP1 expression was evaluated immunohistochemically for nuclear and cytoplasmic staining patterns. ROC analysis identified a cutoff for YAP1 expression, defining tumors with ≥70% nuclear and ≥80% cytoplasmic staining. Results: YAP1 expression had a significant relationship with tumor subtype (p = 0.001), being most frequent in HER-2-positive tumors (55.6%) and least frequent in luminal tumors (11.1%). YAP1 positivity significantly predicted axillary pathological complete response (pCR) (p = 0.01). In YAP1-positive patients, 77.8% achieved axillary pCR compared to 31.7% in YAP1-negative patients, though the YAP1 status and breast pCR association were insignificant (p = 0.07). The Mann–Whitney U test indicated that higher Ki-67 values were significantly associated with positive YAP1 expression (p = 0.028). In contrast, there was no association between ER, PR status, age, and tumor size. Following treatment, there was a statistically significant change in YAP1 expression, with nuclear staining decreasing (p = 0.004) while cytoplasmic staining increased (p = 0.002). YAP1 was significantly linked to axillary pCR, HER-2 status, and Ki-67. Conclusions: Post treatment, nuclear YAP1 decreased, whereas cytoplasmic expression increased, showing a localization shift. These results suggest that YAP1 may predict treatment response and become a future therapeutic target. Full article

Ankyrin repeat domain 1 (Ankrd1), a transcriptional target of Yes-associated protein (YAP), is linked to cardiomyopathy. However, its role in cancer, particularly in clear cell renal cell carcinoma (ccRCC), remains vague. In this study, we examined the expression, regulation, and function of Ankrd1 in ccRCC. High Ankrd1 expression was related to poor prognosis in patients with ccRCC in The Cancer Genome Atlas cohort. Ankrd1 expression was regulated by YAP in all ccRCC cell lines examined and also by ERK5 in a subset of ccRCC cell lines. Moreover, silencing of Ankrd1 in ccRCC cell lines resulted in decreased cell motility, whereas its overexpression increased the cell motility. Ankrd1 colocalized with F-actin in lamellipodia upon phorbol ester stimulation. Ankrd1 silencing resulted in alterations in the shape of RCC cells and caused a decrease in lamellipodia formation. Ankrd1 also colocalized with talin-1 in lamellipodia. Ankrd1 depletion repressed talin-1-mediated activation of the integrin pathway. Immunohistochemical examination of surgical specimens revealed high expression of Ankrd1 in metastatic RCC tissues compared with that in primary RCC tissues from the same patients. Collectively, these findings suggest that Ankrd1 plays a critical role in the motility of ccRCC cells through lamellipodia formation. Full article

Osteoporosis is a prevalent metabolic bone disorder characterized by decreased bone mineral density and increased fracture risk, particularly among aging populations. While conventional pharmacological treatments exist, they often have adverse effects, necessitating the search for alternative therapies. Resveratrol, a naturally occurring polyphenol, has gained significant attention for its potential osteoprotective properties through various molecular mechanisms. This systematic review aims to comprehensively analyze the molecular pathways through which resveratrol protects against osteoporosis. Using an advanced search strategy in the Scopus, PubMed, and Web of Science databases, we identified 513 potentially relevant articles. After title and abstract screening, followed by full-text review, 28 studies met the inclusion criteria. The selected studies comprised 14 in vitro studies, 8 mixed in vitro and in vivo studies, 6 in vivo studies, and 1 cross-sectional study in postmenopausal women. Our findings indicate that resveratrol exerts its osteoprotective effects by enhancing osteoblast differentiation through the activation of the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt), Sirtuin 1 (SIRT1), AMP-Activated Protein Kinase (AMPK), and GATA Binding Protein 1 (GATA-1) pathways while simultaneously inhibiting osteoclastogenesis by suppressing Mitogen-Activated Protein Kinase (MAPK) and TNF Receptor-Associated Factor 6/Transforming Growth Factor-β-Activated Kinase 1 (TRAF6/TAK1). Additionally, resveratrol mitigates oxidative stress and inflammation-induced bone loss by activating the Hippo Signaling Pathway/Yes-Associated Protein (Hippo/YAP) and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) pathways and suppressing Reactive Oxygen Species/Hypoxia-Inducible Factor-1 Alpha (ROS/HIF-1α) and NADPH Oxidase 4/Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (Nox4/NF-κB). Despite promising preclinical findings, the low bioavailability of resveratrol remains a significant challenge, highlighting the need for novel delivery strategies to improve its therapeutic potential. This review provides critical insights into the molecular mechanisms of resveratrol in bone health, supporting its potential as a natural alternative for osteoporosis prevention and treatment. Further clinical studies are required to validate its efficacy and establish optimal dosing strategies. Full article

An actin-binding protein, known as Calponin 3 (CNN3), modulates the remodeling of the actin cytoskeleton, a fundamental process for the maintenance of skeletal muscle homeostasis. Although the roles of CNN3 in actin remodeling have been established, its biological significance in myoblast differentiation remains largely unknown. This study investigated the functional significance of CNN3 in myogenic differentiation, along with its effects on actin remodeling and mechanosensitive signaling in C2C12 myoblasts. CNN3 knockdown led to a marked increase in filamentous actin, which promoted the nuclear localization of Yes-associated protein 1 (YAP1), a mechanosensitive transcriptional coactivator required for response to the mechanical cues that drive cell proliferation. Subsequently, CNN3 depletion enhanced myoblast proliferation by upregulating the expression of the YAP1 target genes related to cell cycle progression, such as cyclin B1, cyclin D1, and PCNA. According to a flow cytometry analysis, CNN3-deficient cells displayed higher S and G2/M phase fractions, which concurred with elevated proliferation rates. Furthermore, CNN3 knockdown impaired myogenic differentiation, as evidenced by reduced levels of MyoD, MyoG, and MyHC, key markers of myogenic commitment and maturation, and immunocytochemistry showed that myotube formation was diminished in CNN3-suppressed cells, which was supported by lower differentiation and fusion indices. These findings reveal that CNN3 is essential for myogenic differentiation, playing a key role in regulating actin remodeling and cellular localization of YAP1 to orchestrate the proliferation and differentiation in myogenic progenitor cells. This study highlights CNN3 as a critical regulator of skeletal myogenesis and suggests its therapeutic potential as a target for muscle atrophy and related disorders. Full article

Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant forms of brain cancer. Current therapeutic strategies, including surgery, chemotherapy, and radiotherapy, often fail due to the tumor’s ability to develop resistance. The proteins YAP-1 (Yes-associated protein 1) and PARP-1 (Poly-(ADP-ribose)–polymerase-1) have been implicated in this resistance, playing crucial roles in cell proliferation and DNA repair mechanisms, respectively. This study explored the inhibitory potential of natural compounds from Lepidium meyenii (Peruvian Maca) on the YAP-1 and PARP-1 protein systems to develop novel therapeutic strategies for GBM. By molecular dynamics simulations, we identified N-(3-Methoxybenzyl)-(9Z,12Z,15Z)- octadecatrienamide (DK5) as the most promising natural inhibitor for PARP-1 and stearic acid (GK4) for YAP-1. Although synthetic inhibitors, such as Olaparib (ODK) for PARP-1 and Verteporfin (VER) for YAP-1, only VER was superior to the naturally occurring molecule and proved a promising alternative. In conclusion, natural compounds from Lepidium meyenii (Peruvian Maca) offer a potentially innovative approach to improve GBM treatment, complementing existing therapies with their inhibitory action on PARP-1 and YAP-1. Full article

Ischemia/reperfusion (I/R) injury with severe cell death is a major complication involved in liver transplantation and resection. The identification of key regulators improving hepatocyte activity may provide potential strategies to clinically resolve I/R-induced injury. N⁶-methyladenosine (m⁶A) RNA modification is essential for tissue homeostasis and pathogenesis. However, the potential involvement of m⁶A in the regulation of hepatocyte activity and liver injury has not been fully explored. In the present study, we found that hepatocyte AlkB homolog H5 (ALKBH5) levels were decreased both in vivo and in vitro I/R models. Hepatocyte-specific ALKBH5 overexpression effectively attenuated I/R-induced liver necrosis and improved cell proliferation in mice. Mechanistically, ALKBH5-mediated m⁶A demethylation improved the mRNA stability of YTH N⁶-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). In conclusion, ALKBH5 is a regulator of hepatic I/R injury that improves hepatocyte repair and proliferation by maintaining YTHDF1 stability and YAP content. The ALKBH5–m⁶A–YTHDF1–YAP axis represents promising therapeutic targets for hepatic I/R injury to improve the prognosis of liver surgery. Full article

Background: Oncogenic mutations in the KRAS gene are detected in >90% of pancreatic cancers (PC). In genetically engineered mouse models of PC, oncogenic KRAS drives the formation of precursor lesions and their progression to invasive PC. The Yes-associated Protein (YAP) is a transcriptional coactivator required for transformation by the RAS oncogenes and the development of PC. In Ras-driven tumors, YAP can also substitute for oncogenic KRAS to drive tumor survival after the repression of the oncogene. Ras oncoproteins exert their transforming properties through their downstream effectors, including the PI3K kinase, Rac1 GTPase, and MAPK pathways. Methods: To identify Ras effectors that regulate YAP, YAP levels were measured in PC cells exposed to inhibitors of oncogenic K-Ras and its effectors. Results: In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132. This YAP degradation after Rac1 inhibition was observed in a range of cell lines using different Rac1 inhibitors, Rac1 siRNA, or expression of dominant negative Rac1^T17N mutant. Several E3 ubiquitin ligases, including SCF^βTrCP, regulate YAP protein stability. To be recognized by this ligase, the βTrCP degron of YAP (amino acid 383–388) requires its phosphorylation by casein kinase 1 at Ser384 and Ser387, but these events must first be primed by the phosphorylation of Ser381 by LATS1/2. Using Flag-tagged mutants of YAP, we show that YAP degradation after Rac1 inhibition requires the integrity of this degron and is blocked by the silencing of βTrCP1/2 and by the inhibition of casein kinase 1. Unexpectedly, YAP degradation after Rac1 inhibition was still observed after the silencing of LATS1/2 or in cells carrying a LATS1/2 double knockout. Conclusions: These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCF^βTrCP ligase but occurs independently of the LATS1/2 kinases. Full article

The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry. We verified CRK-like proto-oncogene adaptor protein (CRKL) as a new YAP-exclusive interaction partner. CRKL is highly expressed in HCC patients, and its expression is associated with YAP activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL-dependent cell survival and the loss of YAP binding induced through actin disruption. Moreover, we delineated the activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data illustrate that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This emphasizes the potential use of targeting the JNK/JUN pathway to suppress YAP expression in HCC patients. Full article

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein–protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome. Full article

In this immunohistological study on the peripheral retina of 3-year-old beagle dogs, excised retina specimens were immunostained with antibodies against nestin, Oct4, Nanog, Sox2, CDX2, cytokeratin 18 (CK 18), RPE65, and YAP1, as well as hematoxylin and DAPI, two nuclear stains. Our findings revealed solitary cysts of various sizes in the inner retina. Intriguingly, a mass of small round cells with scant cytoplasms was observed in the cavity of small cysts, while many disorganized cells partially occupied the cavity of the large cysts. The small cysts were strongly positive for nestin, Oct4, Nanog, Sox2, CDX2, CK18, and YAP1. RPE65-positive cells were exclusively observed in the tissue surrounding the cysts. Since RPE65 is a specific marker of retinal pigment epithelial (RPE) cells, the surrounding cells of the peripheral cysts were presumably derived from RPE cells that migrated intraretinally. In the small cysts, intense positive staining for nestin, a marker of retinal stem cells, seemed to indicate that they were derived from retinal stem cells. The morphology and positive staining for markers of blastocyst and RPE cells indicated that the small cysts may have formed structures resembling the blastocyst, possibly caused by the interaction between retinal stem cells and migrated RPE cells. Full article

Among women, ovarian cancer ranks as the fifth most common cause of cancer-related deaths. This study examined the impact of Hippo signaling pathway on ovarian carcinogenesis. Therefore, the signatures related to Hippo signaling pathway were derived from the molecular signatures database (MSigDB) and were used for further analysis. The Z score-based pathway activation scoring method was employed to investigate the expression patterns of these signatures in the mRNA expression profiles of ovarian cancer cohorts. Compared to other subtype tumors, the results of this study show that the Hippo signaling pathway signatures are dysregulated prominently in serous subtype-specific ovarian carcinogenesis. A receiver operating characteristic (ROC) curve-based results of the Hippo gene set, yes-associated protein 1 (YAP1), and mammalian sterile 20-like kinases 1 (MST1) genes can predict the serous subtype tumors by higher specificity and sensitivity with significant areas under the curve values also further reconfirmed these signaling dysregulations. Moreover, these gene sets were studied further for mutation analysis in the profile of high-grade serous ovarian adenocarcinoma in the cBioPortal database. The OncoPrint results reveal that these Hippo signaling pathway genes are amplified highly during the grade three and stage third or fourth of serous type ovarian tumors. In addition, the results of the Dependency Map (DepMap) plot also clearly show that these genes are amplified significantly across the ovarian cancer cell lines. Finally, overall survival (OS) curve plot investigations also revealed that these gene expressions show poor survival patterns linked to highly expressed conditions in serous subtypes of ovarian cancer patients with significant p-values (p < 0.05). Thus, the current finding would help to develop the targeted therapies treatment for serous subtype ovarian carcinogenesis. Full article

The development of chemotherapy resistance severely limits the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer (PC), and the dysregulation of ferroptosis is a crucial factor in the development of chemotherapy resistance. BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) is highly overexpressed in PC patients and is closely associated with patient prognosis. However, none of the literature reports the connection between BUB1 and ferroptosis. The molecular mechanisms underlying GEM resistance are also not well understood. Therefore, this study first established the high expression levels of BUB1 in PC patients, then explored the role of BUB1 in the process of ferroptosis, and finally investigated the mechanisms by which BUB1 regulates ferroptosis and contributes to GEM resistance in PC cells. In this study, downregulation of BUB1 enhanced the sensitivity of PC cells to Erastin, and inhibited cell proliferation and migration. Mechanistically, BUB1 could inhibit the expression levels of Neurofibromin 2 (NF2) and MOB kinase activator 1 (MOB1), and promote Yes-associated protein (YAP) expression, thereby inhibiting ferroptosis and promoting GEM resistance in PC cells. Furthermore, the combination of BUB1 inhibition with GEM exhibited a synergistic therapeutic effect. These findings reveal the mechanisms underlying the development of GEM chemotherapy resistance based on ferroptosis and suggest that the combined use of BUB1 inhibitors may be an effective approach to enhance GEM efficacy. Full article

Originally identified in Drosophila melanogaster in 1995, the Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by inhibiting proliferation and promoting apoptosis. Large tumor suppressors 1 and 2 (LATS1/2) directly phosphorylate the Yki orthologs YAP (yes-associated protein) and its paralog TAZ (also known as WW domain-containing transcription regulator 1 [WWTR1]), thereby inhibiting their nuclear localization and pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established the role of mis-regulated Hippo signaling in tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development of drug resistances. Hippo signaling components at the heart of oncogenic adaptations fuel the development of drug resistance in many cancers for targeted therapies including KRAS and EGFR mutants. The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA). However, the low response rate and development of drug resistance have posed a major hurdle to improving the progression-free survival (PFS) and overall survival (OS) of cancer patients. Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance. Full article

Promoting rumen development is closely related to the health and efficient growth of ruminants. The transcriptional co-activators Yes1-associated protein (YAP1) and WW domain-containing transcription regulator protein 1 (TAZ) are key regulators of the mammalian epithelium. In the present study, we assessed the impact of YAP1/TAZ on rumen epithelial (RE) cell proliferation using their activator GA-017 (GA) and inhibitor verteporfin (VP). We also investigated whether YAP1/TAZ-dependent alteration was involved in the RE developmental process induced by sodium butyrate (SB). The results indicated that GA promoted RE cell proliferation, while VP disrupted RE cell proliferation. The Hippo, Wnt, and calcium signaling pathways were altered following the regulation of YAP1/TAZ. Upon YAP1/TAZ activation, the expression of CCN1/2 increased. However, when YAP1/TAZ was inhibited, the expression of BIRC3 decreased. In the SB-treated cells, YAP1/TAZ-induced changes were not observed. SB increased the expressions of differentiated cell marker genes and genes involved in short-chain fatty acid (SCFA) metabolism, while YAP1/TAZ did not. Thus, YAP1/TAZ could be potential targets for regulating RE cell proliferation but not for SCFA metabolism. SB could not affect YAP1/TAZ. These findings broaden our understanding of the role of YAP1/TAZ and their regulators in RE development. Full article

The emergence of castration-resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT) is associated with increased malignancy and limited treatment options. This study aims to investigate potential connections between immune cell infiltration and inflammatory cytokines with the YAP1/AR/PSA axis by exploring their interactions with autophagy. Our research reveals heightened levels of Yes-associated protein 1 (YAP1) expression in CRPC tissues compared with tissues from androgen-dependent prostate cancer (ADPC) and benign prostate hyperplasia (BPH). Additionally, a correlation was observed between YAP1 and PSA expressions in CRPC tissues, suggesting that YAP1 may exert a regulatory influence on PSA expression within CRPC. Enhanced YAP1 expression in C4-2 cells resulted in the upregulation of androgen receptor (AR) nuclear translocation and intracellular prostate-specific antigen (PSA) levels. Conversely, the suppression of YAP1 led to a decrease in PSA expression, suggesting that YAP1 may positively regulate the PSA in castration-resistant prostate cancer (CRPC) by facilitating AR nuclear import. The modulation of the autophagy activity exerts a significant impact on the expression levels of YAP1, the AR, and the PSA. Moreover, recent advancements in immunity and inflammation studies present promising avenues for potential therapies targeting prostate cancer (PC). Full article